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.2831T>A (p.Ile944Asn)

CA197176

187262 (ClinVar)

Gene: PALB2

Condition: hereditary breast cancer

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: d59d46f2-098e-4821-b13b-35b21073beb3

HGVS expressions

NM_024675.3:c.2831T>A

NM_024675.3(PALB2):c.2831T>A (p.Ile944Asn)

NC_000016.10:g.23624012A>T

CM000678.2:g.23624012A>T

NC_000016.9:g.23635333A>T

CM000678.1:g.23635333A>T

NC_000016.8:g.23542834A>T

NG_007406.1:g.22346T>A

ENST00000261584.9:c.2831T>A

ENST00000261584.8:c.2831T>A

ENST00000568219.5:c.1946T>A

NM_024675.4:c.2831T>A

NM_024675.4(PALB2):c.2831T>A (p.Ile944Asn)

Uncertain Significance

PM2_Supporting BP1

PS3

Evidence Links 2

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.2831T>A variant in PALB2 is a missense variant predicted to cause substitution of isoleucine by asparagine at amino acid 944 (p.Ile944Asn). This variant is absent from gnomAD v2.1.1. This variant is non-functional in multiple different protein assays (PMID: 31757951, 31636395); 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 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. (PM2_Supporting, BP1)

PM2_Supporting

Variant is absent in the 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.

PS3

This variant is non-functional in multiple different protein assays (PMIDs: 31757951, 31636395); however due to a lack of known positive controls, do not apply functional criteria at this time.

This variant had <40% homologous recombination efficiency relative to wildtype which is below the threshold for a non-functional variant (PMID 31757951; PS3_Moderate) PubMed:31757951

This variant had ≤1.7 fold change in a homology directed DNA repair assay which is below the threshold for a non-functional variant (PMID 31636395; PS3_Supporting) PubMed:31636395

Approved on: 2023-04-05

Published on: 2023-04-07

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