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


Variant: NM_024675.3(PALB2):c.2027T>C (p.Ile676Thr)

CA294362

142310 (ClinVar)

Gene: PALB2
Condition: hereditary breast cancer
Inheritance Mode: Autosomal dominant inheritance
UUID: 09e52437-a25c-47bf-bb56-3a3aeed7872d
Approved on: 2023-04-05
Published on: 2023-04-07

HGVS expressions

NM_024675.3:c.2027T>C
NM_024675.3(PALB2):c.2027T>C (p.Ile676Thr)
NC_000016.10:g.23630127A>G
CM000678.2:g.23630127A>G
NC_000016.9:g.23641448A>G
CM000678.1:g.23641448A>G
NC_000016.8:g.23548949A>G
NG_007406.1:g.16231T>C
ENST00000261584.9:c.2027T>C
ENST00000261584.8:c.2027T>C
ENST00000565038.1:n.87-852T>C
ENST00000568219.5:c.1142T>C
NM_024675.4:c.2027T>C
NM_024675.4(PALB2):c.2027T>C (p.Ile676Thr)

Benign

Met criteria codes 3
BP1 BA1 BS2
Not Met criteria codes 5
BP4 PP3 PM2 PM3 BS3

Evidence Links 1

Expert Panel

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.2027T>C variant in PALB2 is a missense variant predicted to cause a substitution of isoleucine by threonine at amino acid 676 (p.Ile676Thr). This variant has been observed in the homozygous state in multiple individuals without Fanconi Anemia (Ambry Genetics). This variant has a gnomAD v.2.1.1 filtering allele frequency of 0.005 in the Latino/Admixed American population, which is higher than the HBOP VCEP threshold (>0.001) for BA1, and therefore meets this criterion. This variant is functional in a protein assay (PMID 33964450); 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. 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 benign 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. (BA1, BS2, BP1)
Met criteria codes
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 (BP1)
BA1
This variant has a GnomAD (v2.1.1) filtering allele frequency of 0.5% (Latino/Admixed American) which is above the PALB2 BA1 threshold of 0.1% (BA1).
BS2
This variant has been observed in a homozygous and/or compound heterozygous state (confirmed) in multiple individuals without Fanconi-Anemia (Ambry Genetics). (BS2_strong) (6 pts)
Not Met criteria codes
BP4
No splicing impact predicted by SpliceAI. Protein in silico is not a line of evidence for PALB2.
PP3
No splicing impact predicted by SpliceAI. Protein in silico is not a line of evidence for PALB2.
PM2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
Homology-directed repair function in HEK293T cells showed 1.214 mean HR/NHEJ reading, which falls in the authors threshold for a normal protein function (PMID 33964450). However, this assay does not meet the requirements for use by the HBOP VCEP.

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