Submissions for variant NM_000059.4(BRCA2):c.2987T>G (p.Leu996Arg)

gnomAD frequency: 0.00004  dbSNP: rs80358545

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113125	SCV001161613	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-06-18	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000661
Invitae	RCV000167829	SCV000072111	likely benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000130463	SCV000185328	likely benign	Hereditary cancer-predisposing syndrome	2018-10-01	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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	RCV000679165	SCV000210584	likely benign	not provided	2020-06-01	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22753899, 23929434, 31131967, 25682074)
Illumina Laboratory Services, Illumina	RCV000113125	SCV000383669	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	RCV000324539	SCV000383670	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.
Color Diagnostics, LLC DBA Color Health	RCV000130463	SCV000688782	likely benign	Hereditary cancer-predisposing syndrome	2016-12-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679165	SCV000805682	likely benign	not provided	2017-12-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044098	SCV000918960	likely benign	not specified	2021-12-14	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.2987T>G (p.Leu996Arg) 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 3.6e-05 in 250570 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2987T>G has been reported in the literature once in a cohort of 493 Australian patients with triple negative breast cancer (Wong-Brown_2015). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant has been reported (BRCA2 legacy name 4075delGT, c.3847_3848delGT, p.Val1283fsX2) in a patient affected with ovarian cancer with a family history significant for breast cancer in two sisters and in two nieces all of whom were positive for BRCA2 mutation (Root_2012). These data provide supporting evidence for a benign role of the variant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a majority consensus leaning towards a likely benign/benign outcome (n=8) (VUS, n=2). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679165	SCV001133731	uncertain significance	not provided	2018-11-21	criteria provided, single submitter	clinical testing
Mendelics	RCV000113125	SCV001139052	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000679165	SCV001471052	likely benign	not provided	2019-12-21	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130463	SCV002533753	likely benign	Hereditary cancer-predisposing syndrome	2021-12-28	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000044098	SCV004027414	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113125	SCV000146156	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000113125	SCV004243598	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing