Submissions for variant NM_000059.4(BRCA2):c.3581G>A (p.Gly1194Asp) (rs28897721)

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)	RCV000077309	SCV000244439	benign	Breast-ovarian cancer, familial 2	2015-08-10	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 = 0.0000646
Invitae	RCV001084719	SCV000072240	benign	Hereditary breast and ovarian cancer syndrome	2019-12-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131681	SCV000186717	likely benign	Hereditary cancer-predisposing syndrome	2018-10-26	criteria provided, single submitter	clinical testing	Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;In silico models in agreement (benign);Other data supporting benign classification
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario	RCV000735541	SCV000219329	likely benign	Breast and/or ovarian cancer	2017-02-07	criteria provided, single submitter	clinical testing
Counsyl	RCV000077309	SCV000487793	benign	Breast-ovarian cancer, familial 2	2015-11-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000440462	SCV000518131	likely benign	not specified	2017-08-15	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.
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV000440462	SCV000591870	benign	not specified	2012-09-05	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000440462	SCV000694707	benign	not specified	2020-11-09	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3581G>A (p.Gly1194Asp) results in a non-conservative amino acid change located in the BRCA2 repeat region of 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 8.7e-05 in 252186 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (8.7e-05 vs 0.00075), allowing no conclusion about variant significance. c.3581G>A, has been reported in the literature in individuals affected with Breast and Ovarian Cancer (e.g. Alsop 2012, Musolino 2007), without strong evidence for pathogenicity. The variant was predicted to be neutral with a multifactorial probability model, based on tumor pathology, clinical histories, family studies and co-occurrence with deleterious mutations (Easton 2007). In addition, UMD BRCA2 database classified this variant as 'likely neutral'. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least two co-occurrences with other pathogenic variant(s) have been observed (BRCA2 c.5130_5133delTGTA, p.Y1710* at our laboratory; TP53 c.524G>A , p.R175H in a family with Li-Fraunemi syndrome, Zampiga_2016), providing supporting evidence for a benign role. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign, n=3, likely benign, n=5, VUS, n=1). Based on the lack of any actionable evidence supporting a pathogenic outcome as outlined above, the variant was classified as benign.
Color Health, Inc	RCV000131681	SCV000902800	likely benign	Hereditary cancer-predisposing syndrome	2015-11-08	criteria provided, single submitter	clinical testing
Mendelics	RCV000077309	SCV001139068	likely benign	Breast-ovarian cancer, familial 2	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV001111917	SCV001269525	uncertain significance	Fanconi anemia, complementation group D1	2019-05-20	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina	RCV000077309	SCV001269526	uncertain significance	Breast-ovarian cancer, familial 2	2019-05-20	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Biesecker Lab/Clinical Genomics Section,National Institutes of Health	RCV000034439	SCV000043207	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
Sharing Clinical Reports Project (SCRP)	RCV000077309	SCV000109106	uncertain significance	Breast-ovarian cancer, familial 2	2008-05-02	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077309	SCV000146262	uncertain significance	Breast-ovarian cancer, familial 2	2002-05-29	no assertion criteria provided	clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735541	SCV000863679	uncertain significance	Breast and/or ovarian cancer		no assertion criteria provided	clinical testing