ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.571G>A (p.Val191Ile) (rs80357090)

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Total submissions: 15
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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 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
Invitae RCV001083276 SCV000077076 benign Hereditary breast and ovarian cancer syndrome 2020-12-06 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: 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 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,PreventionGenetics RCV000123886 SCV000806978 benign not specified 2017-03-20 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162499 SCV000910664 benign Hereditary cancer-predisposing syndrome 2016-01-22 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000031265 SCV001284090 likely benign Breast-ovarian cancer, familial 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 Praxis fuer Humangenetik Tuebingen RCV000586929 SCV001501185 likely benign not provided 2021-01-01 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031265 SCV000053870 benign Breast-ovarian cancer, familial 1 2008-09-16 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031265 SCV000145630 uncertain significance Breast-ovarian cancer, familial 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 1 no assertion criteria provided clinical testing

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