Submissions for variant NM_000059.4(BRCA2):c.7402G>A (p.Val2468Ile)

gnomAD frequency: 0.00001  dbSNP: rs730881553

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160129	SCV000210419	uncertain significance	not provided	2023-06-28	criteria provided, single submitter	clinical testing	Observed in at least one individual referred for hereditary cancer genetic testing (Apessos et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 7630G>A; This variant is associated with the following publications: (PMID: 23525077, 32377563, 29884841, 29310832)
Ambry Genetics	RCV000217429	SCV000273805	likely benign	Hereditary cancer-predisposing syndrome	2020-01-10	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000538908	SCV000635570	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 2468 of the BRCA2 protein (p.Val2468Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary breast and ovarian cancer (PMID: 29310832). ClinVar contains an entry for this variant (Variation ID: 182237). 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. 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.
Color Diagnostics, LLC DBA Color Health	RCV000217429	SCV000911804	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-08	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 2468 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 family with suspected hereditary breast and ovarian cancer syndrome (PMID: 29310832). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001199869	SCV001370608	uncertain significance	not specified	2020-05-07	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7402G>A (p.Val2468Ile) results in a conservative amino acid change located in the Breast cancer type 2 susceptibility protein, helical domain (IPR015252) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251032 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7402G>A has been reported in the literature in at least one individual affected with Hereditary Breast and Ovarian Cancer Syndrome (Apessos_2018). This report however, does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.