ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5005G>T (p.Ala1669Ser) (rs80357087)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001079653 SCV000076749 benign Hereditary breast and ovarian cancer syndrome 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130911 SCV000185820 likely benign Hereditary cancer-predisposing syndrome 2018-09-26 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);Intact protein function observed in appropriate functional assay(s);Other data supporting benign classification
GeneDx RCV000048736 SCV000209983 likely benign not specified 2017-09-11 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.
Counsyl RCV000112461 SCV000220738 likely benign Breast-ovarian cancer, familial 1 2014-09-26 criteria provided, single submitter literature only
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000414907 SCV000492641 uncertain significance Breast carcinoma 2015-11-13 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000048736 SCV000538451 uncertain significance not specified 2016-06-23 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Multiple reports describe as nonpathogenic; ClinVar: 4 B/LB, 2 VUS
Genetic Services Laboratory, University of Chicago RCV000048736 SCV000593657 likely benign not specified 2016-10-26 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130911 SCV000683240 likely benign Hereditary cancer-predisposing syndrome 2016-07-20 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000034757 SCV000699192 benign not provided 2016-03-23 criteria provided, single submitter clinical testing Variant Summary: The variant of interest causes a missense change involving a conserved nucleotide with 3/4 in silico programs (SNPs&Go effect not captured here due to low reliability index) predict a "deleterious" outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency 6/121254 (1/20210), which does not exceed the predicted maximum expected allele frequency for a pathogenic BRCA1 variant of 1/1000. The variant of interest has been reported in affected individuals via publications including a co-occurrence with another pathogenic BRCA1 variant 2080delA (Judkins_2005) and a lack of co-segregation with disease (Vallon-Christersson_2001). Multiple functional studies showed the variant of interest to act comparable to wild type. In addition, multiple reputable databases/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.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197438 SCV001368178 likely benign Familial cancer of breast 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Likely benign. The following ACMG criteria were applied in classifying this variant: PM1,PP3,BP6,BS1.
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034757 SCV000043152 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112461 SCV000145259 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
CSER _CC_NCGL, University of Washington RCV000148380 SCV000190078 likely benign Breast and/or ovarian cancer 2014-06-01 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353726 SCV000591561 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Ala1669Ser variant was identified in 1 of 208 proband chromosomes (frequency: 0.005) from individuals or families with breast and ovarian cancer (Stegel 2011).The variant was also identified in dbSNP (ID: rs80357087) “With Uncertain significance allele”, NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC) database, LOVD, the ClinVar database (classified as a uncertain significance variant by the BIC, Biesecker Laboratory; classified as likely benign by Ambry Genetics, CSER_CC_NCGL, GeneDX, Counsyl), the BIC database (11X with unknown clinical importance), and UMD (1X as a UV variant).This variant was identified in the Exome Variant Server project in 1 of 8600 European American alleles, the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 6 of 77032 chromosomes (6 individuals) from a population of European (Non-Finnish /African individuals, although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The p.Ala1669 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. Comprehensive analysis study by Lee (2010) identified the variant score no protein folding defect, normal peptide binding activity and specificity, and normal transcriptional activity. The study by Rowling (2010) used biophysical approach to classify the variant and suggested the variant does not have destabilizing effect. Furthermore, conservation analysis by Abkevich (2004) classified the variant as likely to be neutral or of little clinical significance. In addition, this variant was identified in trans with known deleterious mutations (2080delA) (Judkins 2005), increasing the likelihood this variant does not have clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as predicted benign.
Brotman Baty Institute,University of Washington RCV000112461 SCV001243923 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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