Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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Variant: NM_024675.3(PALB2):c.3089C>T (p.Thr1030Ile)

CA10579934

232977 (ClinVar)

Gene: PALB2

Condition: hereditary breast cancer

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 38463071-c698-4ef3-b991-32986b9189e9

HGVS expressions

NM_024675.3:c.3089C>T

NM_024675.3(PALB2):c.3089C>T (p.Thr1030Ile)

NC_000016.10:g.23621386G>A

CM000678.2:g.23621386G>A

NC_000016.9:g.23632707G>A

CM000678.1:g.23632707G>A

NC_000016.8:g.23540208G>A

NG_007406.1:g.24972C>T

ENST00000261584.9:c.3089C>T

ENST00000261584.8:c.3089C>T

ENST00000566069.5:n.4C>T

ENST00000568219.5:c.2204C>T

NM_024675.4:c.3089C>T

NM_024675.4(PALB2):c.3089C>T (p.Thr1030Ile)

Uncertain Significance

PM2_Supporting BP1 BS2_Supporting

BS3 BS1 BP4 PS3 PP3 BA1

Evidence Links 5

Expert Panel

Hereditary Breast, Ovarian and Pancreatic Cancer VCEP

Criteria Specification Information

Criteria Specification: ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PALB2 Version 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Hereditary Breast, Ovarian and Pancreatic Cancer VCEP

The c.3089C>T variant in PALB2 is a missense variant predicted to cause a substitution of threonine for isoleucine at amino acid 1030 (p.Thr1030Ile). This variant has been observed with another variant in PALB2 that is tentatively classified as likely pathogenic by HBOP VCEP in an individual without Fanconi Anemia (Ambry Genetics). The phase of the variants was not determined. This variant has been tested in multiple protein assays (PMID 33964450, 31636395, 31757951, 31586400); however due to a lack of positive missense controls with known clinical impact, these protein assays do not meet the requirements for use by the HBOP VCEP. This variant is absent from gnomAD v2.1.1. PALB2, in which the variant was identified, is defined by the HBOP VCEP as a gene for which primarily truncating variants are known to cause disease. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (BS2_supporting, PM2_supporting, BP1)

PM2_Supporting

This variant is absent from gnomAD v2.1.1 (PM2_Supporting).

BP1

PALB2, in which the variant was identified, is defined by the HBOP VCEP as a gene for which primarily truncating variants are known to cause disease.

BS2_Supporting

This variant has been observed with a likely pathogenic variant in PALB2 (Ambry genetics; 61756) in an individual without Fanconi anemia. The phase of the variants was not determined, (BS2_supporting). 1 POINTS:

BS3

Multiple studies showed a normal protein function (33964450, 31636395). However, due to a lack of known positive missense controls with known clinical impact, protein assays do not meet the requirements for use by the HBOP VCEP

PARP inhibitor sensitivity function in HeLa cells showed 58% survival relative to WT, which falls in the indeterminant range established by the HBOP VCEP. Mammalian two-hybrid in HEK293 cells showed <10% BRCA2 binding, which falls in the abnormal function rage established by the HBOP VCEP. RAD51C foci formation in HeLa cells showed 56% decreased in foci number and 59% decrease in intensity per focus, which falls in the indeterminant function range established by the HBOP VCEP. Homology-directed repair function in U2OS cells showed 23.6% activity of WT, which falls in the indeterminant function range established by the HBOP VCEP. However due to a lack of known positive missense controls with known clinical impact, protein assays do not meet the requirements for use by the HBOP VCEP PubMed:31586400

In vitro binding assay: T10301 shows "statistically significant" reduction in RAD51C, RAD51 interaction, but not BRCA2 or XRCC3. Translation inhibition with CHX shows reduced stability of T10301I that is restored by treatment with proteosome inhibitor (MG132); suggesting the T1030I is degraded in a proteasome dependent manner. However, due to a lack of known positive missense controls with known clinical impact, protein assays do not meet the requirements for use by the HBOP VCEP PubMed:24141787

Homology-directed repair function in HEK293T cells showed 0.859 mean HR/NHEJ reading, which falls in the authors threshold for a normal protein function (PMID 33964450). However due to a lack of known positive missense controls with known clinical impact, protein assays do not meet the requirements for use by the HBOP VCEP PubMed:33964450

Homology-directed repair function in B400 mouse mammary tumor cells showed 3.0 normalized fold change, which falls in the normal function range established by the HBOP VCEP. However due to a lack of known positive missense controls with known clinical impact, protein assays do not meet the requirements for use by the HBOP VCEP PubMed:31636395

Homology-directed repair function in mES cells showed 14.68% relative efficiency, which falls in the threshold for an abnormal protein function established by the HBOP VCEP. PARP inhibitor sensitivity function in mES cells showed 14.8% relative resistance to PARPi, which falls in the threshold for an abnormal protein function established by the HBOP VCEP. However due to a lack of known positive missense controls with known clinical impact, protein assays do not meet the requirements for use by the HBOP VCEP PubMed:31757951

BS1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BP4

No predicted impact on splicing. Protein in silico N/A for PALB2

PS3

Multiple studies showed an abnormal protein function (31757951, 31586400). However, due to a lack of known positive missense controls with known clinical impact, protein assays do not meet the requirements for use by the HBOP VCEP

PP3

Protein in silico N/A for PALB2

BA1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Approved on: 2023-04-05

Published on: 2023-04-07

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