Submissions for variant NM_000059.4(BRCA2):c.1625T>C (p.Ile542Thr)

dbSNP: rs397507273

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000222475	SCV000278478	likely benign	Hereditary cancer-predisposing syndrome	2024-01-09	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589631	SCV000694549	uncertain significance	not provided	2017-05-15	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.1625T>C (p.Ile542Thr) variant involves the alteration of a non-conserved nucleotide and 3/5 in silico tools predict a benign outcome. However, these predictions have yet to be functionally assessed. This variant was found in 1/121012 control chromosomes (ExAC) at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). In addition, multiple clinical diagnostic laboratories classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
Color Diagnostics, LLC DBA Color Health	RCV000222475	SCV001353455	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-10	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 542 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/250880 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001222108	SCV001394191	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-09-16	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 542 of the BRCA2 protein (p.Ile542Thr). This variant is present in population databases (rs397507273, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 37750). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000222475	SCV003851528	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Myriad Genetics, Inc.	RCV000031331	SCV004931799	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2024-02-26	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Sharing Clinical Reports Project (SCRP)	RCV000031331	SCV000053936	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2009-03-27	no assertion criteria provided	clinical testing