Submissions for variant NM_007294.4(BRCA1):c.571G>A (p.Val191Ile)

gnomAD frequency: 0.00021  dbSNP: rs80357090

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031265	SCV000244408	benign	Breast-ovarian cancer, familial, susceptibility to, 1	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 = 0.000000157
Labcorp Genetics (formerly Invitae), Labcorp	RCV001083276	SCV000077076	benign	Hereditary breast ovarian cancer syndrome	2024-01-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000123886	SCV000167231	benign	not specified	2013-12-16	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.
Ambry Genetics	RCV000162499	SCV000212887	benign	Hereditary cancer-predisposing syndrome	2014-11-18	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Pathway Genomics	RCV000031265	SCV000223750	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-10-30	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000586929	SCV000602666	benign	not provided	2017-10-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586929	SCV000699276	benign	not provided	2016-03-28	criteria provided, single submitter	clinical testing	Variant Summary: The variant of interest causes a missense change involving a non-conserved nucleotide with 3/4 in silico programs (SNPs&GO not captured here due to low reliability index) predict a "benign" outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 36/121098 (1/3363), predominantly in the East Asian cohort, 29/8636 (1/297), which exceeds the predicted maximum expected allele frequency for a pathogenic BRCA1 variant of 1/1000. Therefore, suggesting that the variant of interest is a polymorphism found in population(s) of East Asian origin. The variant of interest has been reported in multiple affected individuals via publications and databases including multiple reported co-occurrences with a pathogenic BRCA1 variant, c.181T>G (p.Cys61Gly classified as pathogenic by LCA) and c.188T>A (p.L63X), and a pathogenic BRCA2 variant, c.9382C>T (p.R3128X). Functional studies show that the variant acts comparable to wild type function (Bouwman_2013, Lu_2015). In addition, multiple reputable clinical laboratories cite the variant with a classification of "likely benign/benign." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign.
PreventionGenetics, part of Exact Sciences	RCV000123886	SCV000806978	benign	not specified	2017-03-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162499	SCV000910664	benign	Hereditary cancer-predisposing syndrome	2016-01-22	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000031265	SCV001284090	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2017-04-27	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV000586929	SCV001501185	likely benign	not provided	2021-01-01	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV001083276	SCV002026019	benign	Hereditary breast ovarian cancer syndrome	2021-11-16	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798035	SCV002043460	likely benign	Breast and/or ovarian cancer	2022-09-06	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162499	SCV002537875	likely benign	Hereditary cancer-predisposing syndrome	2020-12-09	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000123886	SCV002551050	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496478	SCV002808658	likely benign	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2022-05-10	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031265	SCV000053870	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2008-09-16	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031265	SCV000145630	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353887	SCV000591287	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Val191Ile was identified in the literature in 9 of 1620 proband chromosomes (frequency: 0.006) from individuals with breast or ovarian cancer (Ang 2007, Chang 2001, Haffty 2009, Purnomosari 2007, Sng 2000, Thirthagiri 2008). The variant was also identified in dbSNP “With non-pathogenic allele” (ID: rs80357090), HGMD, LOVD, UMD (3X as a neutral variant), and the BIC database (10X with unknown clinical importance). This variant was reported with allelic frequencies of 0.001 and 0.0003 in the 1000 Genomes Project and Exome Variant Server ESP Project respectively, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. In addition, the variant was shown by Judkins (2005) to reside in trans with a known BRCA1 deleterious mutation (p.Leu63X), increasing the likelihood that the p.Val191Ile variant does not have clinical importance. Furthermore, Myriad classifies this variant as a “non-reportable polymorphism” (personal communication). Although the p.Val191 residue is conserved in mammals, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) do not suggest that the p.Val191Ile variant has a high likelihood of impact to the protein, and two in silico studies suggest that this variant is not pathogenic or of no clinical significance (Easton 2007, Lindor 2012). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000031265	SCV000733668	benign	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000123886	SCV001927445	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000123886	SCV001957376	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000123886	SCV001968904	benign	not specified		no assertion criteria provided	clinical testing
Center for Precision Medicine, Meizhou People's Hospital	RCV002250482	SCV002520909	likely benign	Familial cancer of breast		no assertion criteria provided	literature only