Submissions for variant NM_000059.4(BRCA2):c.6540G>C (p.Leu2180Phe)

gnomAD frequency: 0.00001  dbSNP: rs398122560

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131800	SCV000186851	likely benign	Hereditary cancer-predisposing syndrome	2018-08-31	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.
GeneDx	RCV000160235	SCV000210630	likely benign	not specified	2016-11-07	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000234409	SCV000283294	likely benign	Hereditary breast ovarian cancer syndrome	2023-12-22	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000160235	SCV000593725	likely benign	not specified	2015-10-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131800	SCV000688985	likely benign	Hereditary cancer-predisposing syndrome	2015-03-11	criteria provided, single submitter	clinical testing
Counsyl	RCV000076969	SCV000785830	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-12-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000076969	SCV001267259	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001109883	SCV001267260	uncertain significance	Fanconi anemia complementation group D1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000160235	SCV001360958	uncertain significance	not specified	2023-11-20	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6540G>C (p.Leu2180Phe) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.2e-06 in 244134 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6540G>C has been reported in the literature in at least one individual affected with Hereditary Breast And Ovarian Cancer Syndrome (Meisel_2017, Sadowski_2017). These reports do 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. Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as either likely benign (n=6) or VUS (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000131800	SCV003847252	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).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477474	SCV004220511	uncertain significance	not provided	2023-03-01	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.0000082 (2/244134 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in families with hereditary breast and/or ovarian cancer (PMID: 28324225 (2017), 28807866 (2017)). In a large-scale breast cancer association study, the variant was observed in an unaffected individual (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). It is also predicted to have a low probability of being pathogenic using a Bayesian hierarchical method (PMID: 18418466 (2005)). 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.
All of Us Research Program, National Institutes of Health	RCV000076969	SCV004844278	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2024-02-05	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000076969	SCV000108766	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-04-24	no assertion criteria provided	clinical testing