Submissions for variant NM_000059.4(BRCA2):c.7252A>G (p.Arg2418Gly)

dbSNP: rs80358953

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045176	SCV000073189	likely benign	Hereditary breast ovarian cancer syndrome	2024-12-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000163032	SCV000213520	likely benign	Hereditary cancer-predisposing syndrome	2019-01-31	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	RCV000113740	SCV000487827	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-11-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000443470	SCV000527881	likely benign	not specified	2016-05-12	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586914	SCV000695051	uncertain significance	not provided	2016-12-05	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.7252A>G (p.Arg2418Gly) variant involves the alteration of a non-conserved nucleotide. 3/5 in silico tools predict a benign outcome for this variant. This variant is absent in 121330 control chromosomes. The variant has been reported in publications, without strong evidence for causality, and was considered likely benign using a multifactorial based model (Lindor_2012). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign, without evidence to independently evaluate. Taken together, this variant is classified as VUS.
Color Diagnostics, LLC DBA Color Health	RCV000163032	SCV001359210	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-12	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glycine at codon 2418 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant protein moderately increases the sensitivity to PARP inhibitors in mammalian cells compared to the wild-type protein (PMID: 32444794). This variant has been reported in at least one individual affected with breast cancer (PMID: 18824701). 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.
All of Us Research Program, National Institutes of Health	RCV000113740	SCV004844384	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-11-02	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glycine at codon 2418 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant protein moderately increases the sensitivity to PARP inhibitors in mammalian cells compared to the wild-type protein (PMID: 32444794). This variant has been reported in at least one individual affected with breast cancer (PMID: 18824701). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586914	SCV005625276	uncertain significance	not provided	2024-10-26	criteria provided, single submitter	clinical testing	The BRCA2 c.7252A>G (p.Arg2418Gly) variant has been reported in the published literature in one individual with an unspecified solid tumor (PMID: 38795236 (2024)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113740	SCV000147061	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing