ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.314A>G (p.Tyr105Cys) (rs28897673)

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Total submissions: 14
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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) RCV000112301 SCV000244336 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 = 0.000000105
Invitae RCV000048083 SCV000076096 benign Hereditary breast and ovarian cancer syndrome 2020-12-07 criteria provided, single submitter clinical testing
GeneDx RCV000123881 SCV000167226 benign not specified 2013-11-05 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 RCV000162964 SCV000213452 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.
Counsyl RCV000112301 SCV000220600 likely benign Breast-ovarian cancer, familial 1 2014-08-19 criteria provided, single submitter literature only
Michigan Medical Genetics Laboratories,University of Michigan RCV000112301 SCV000267679 benign Breast-ovarian cancer, familial 1 2016-04-21 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162964 SCV000683088 likely benign Hereditary cancer-predisposing syndrome 2015-02-17 criteria provided, single submitter clinical testing
Mendelics RCV000048083 SCV000839307 likely benign Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Mendelics RCV000112301 SCV001140638 likely benign Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000112301 SCV001285180 likely benign Breast-ovarian cancer, familial 1 2017-04-28 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286871 SCV001473492 benign none provided 2020-03-17 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112301 SCV000145035 benign Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
CSER _CC_NCGL, University of Washington RCV000148385 SCV000190083 likely benign Breast neoplasm 2014-06-01 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354379 SCV001548985 likely benign Endometrial carcinoma no assertion criteria provided clinical testing The BRCA1 p.Tyr105Cys variant was identified in 4 of 6744 proband chromosomes (frequency: 0.0006) from American, Spanish, Moroccan and Portuguese individuals or families with breast and breast/ovarian cancer (Borg_2010_20104584, Diez_2003_12955716, Laraqui_2013_23289006, Peixoto_2015_24916970). A hierarchcal statistical model of the data in the case control study (Borg_2010_20104584), found the variant to be neutral (Capanu_2011_21520273). A cDNA-based functional assay looking at the variant’s ability to functionally complement BRCA1-deficient mouse embryonic stem cells found the variant to be neutral, showing protein levels and cisplatin response comparable to wildtype (Bouwman_2013_23867111). In another functional assay looking at homology directed repair and single-strand annealing, the variant showed an intermediate phenotype, neither fully active nor fully defective, thereby classifying it as uncertain significance (Towler_2013_23161852). Using a method combining the bioinformatics tool A-GVGD, which assesses variation present at a missense position against multiple sequence alignments, and any co-occurrences with the variant, the variant was classified as uncertain significance (Tavtigian_2006_16014699). Two bioinformatics models that calculate posterior probability and likelihood ratio of pathogenicity, both integrating multiple forms of genetic evidence, found the variant to be not pathogenic or neutral (Lindor_2012_21990134, Easton_2007_17924331). The variant was also identified in dbSNP (ID: rs28897673) “With Likely benign allele”, ClinVar (benign, reviewed by an expert panel (2015); submitters: benign by ENIGMA, Michigan Medical Genetics Laboratories (University of Michigan), Ambry Genetics, Invitae, GeneDx, and BIC, and likely benign by Counsyl and CSER_CC_NCGL(University of Washington)), Clinvitae (5x), COGR (by 3 clinical labs classified as benign/likely benign and uncertain significance), LOVD 3.0, UMD-LSDB (22x as 1-neutral, co-occurring with a BRCA1 pathogenic variant (c.IVS6+1G>T/c.516+1G>T)), BIC Database (18x with no clinical importance, classification pending), ARUP Laboratories (not pathogenic, or of no clinical importance), and was not identified in Cosmic, MutDB, or Zhejiang Colon Cancer Database. The variant also co-occurred in trans with known pathogenic BRCA1 variants (623del5 and 5385insC) (Judkins_2005_16267036). The variant was identified in control databases in 19 of 245822 chromosomes at a frequency of 0.00008 (Genome Aggregation Database Feb 27, 2017). Observation by population included: “Other” in 2 of 5482 chromosomes (freq: 0.0004), Latino in 3 of 33552 chromosomes (freq: 0.00009), European Non-Finnish in 14 of 111554 chromosomes (freq: 0.0001); it was not observed in the African, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Tyr105 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood the Cys variant impacts the protein; however, this information is not predictive enough to rule out 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. 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 likely benign.

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