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]

Link to SEPIO compliant JSON-LD document

Variant: NM_024675.4:c.2734T>G

CA395121845

Gene: PALB2

Condition: hereditary breast cancer

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 7bbe313d-b343-4055-b882-bf9f9b9813aa

HGVS expressions

NM_024675.4:c.2734T>G

NC_000016.10:g.23626250A>C

CM000678.2:g.23626250A>C

NC_000016.9:g.23637571A>C

CM000678.1:g.23637571A>C

NC_000016.8:g.23545072A>C

NG_007406.1:g.20108T>G

ENST00000261584.9:c.2734T>G

ENST00000261584.8:c.2734T>G

ENST00000565038.1:n.306T>G

ENST00000568219.5:c.1849T>G

NM_024675.3:c.2734T>G

Uncertain Significance

PM2_Supporting BP1

PS3 BA1 PP3 BS1 BP4

Evidence Links 1

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.2734T>G variant in PALB2 is a missense variant predicted to cause a substitution of tryptophan by glycine at amino acid 912 (p.Trp912Gly). This variant is absent in the gnomAD v2.1.1 cohort. This variant showed an abnormal read out in multiple protein assays (PMID 31757951); 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 VUS 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. (PM2_supporting, BP1)

PM2_Supporting

This variant is absent from gnomAD v(2.1.1) (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 (BP1).

PS3

This variant showed an abnormal read out in multiple protein assays (PMID 31757951); 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.

Homology-directed repair function in mES cells showed 6.6% 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 7.73% 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

BA1

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

PP3

SpliceAI= no predicted impact on splicing. In silico protein predictions N/A for PALB2 classification.

BS1

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

BP4

SpliceAI= no predicted impact on splicing. In silico protein predictions N/A for PALB2 classification.

Approved on: 2023-04-05

Published on: 2023-04-07

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.