Submissions for variant NM_000059.4(BRCA2):c.9307A>G (p.Ile3103Val)

dbSNP: rs80359203

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162720	SCV000213182	likely benign	Hereditary cancer-predisposing syndrome	2021-06-09	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.
Counsyl	RCV000077468	SCV000785126	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-05-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162720	SCV001354226	uncertain significance	Hereditary cancer-predisposing syndrome	2022-05-06	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 3103 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 been reported in 1 individual affected with breast cancer (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000445). This variant has not been identified 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	RCV001295985	SCV001484939	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-05-01	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 3103 of the BRCA2 protein (p.Ile3103Val). This variant is not present in population databases (gnomAD no frequency). 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: 52810). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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.
GeneDx	RCV001753460	SCV002005345	uncertain significance	not provided	2019-07-22	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19043619)
All of Us Research Program, National Institutes of Health	RCV004803937	SCV005425845	uncertain significance	BRCA2-related cancer predisposition	2024-08-06	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 3103 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 been reported in 1 individual affected with breast cancer (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000445). This variant has not been identified 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.
Sharing Clinical Reports Project (SCRP)	RCV000077468	SCV000109266	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2010-05-26	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077468	SCV000147607	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2011-10-19	no assertion criteria provided	clinical testing