ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4204C>T (p.His1402Tyr) (rs80357365)

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Total submissions: 11
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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) RCV000083205 SCV000244356 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 = 0.000187
Invitae RCV001087632 SCV000076499 benign Hereditary breast and ovarian cancer syndrome 2020-10-03 criteria provided, single submitter clinical testing
GeneDx RCV000254639 SCV000209970 likely benign not specified 2016-10-21 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 RCV000162983 SCV000213471 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 RCV000083205 SCV000220709 likely benign Breast-ovarian cancer, familial 1 2014-09-18 criteria provided, single submitter literature only
Color Health, Inc RCV000162983 SCV000683161 likely benign Hereditary cancer-predisposing syndrome 2017-06-19 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000254639 SCV000699119 benign not specified 2019-08-16 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4204C>T (p.His1402Tyr) results in a conservative amino acid change in 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 4e-06 in 252354 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.4204C>T, has been reported in the literature in individuals affected with breast cancer (Eng_2001, Hondow_2011). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variants have been reported (BRCA1 c.5263_5264insC, p.Ser1755?fs; BRCA2 c.8167G>C, p.Asp2723His; PMS2 c.137G>T, p.Ser46Ile; BRCA1 c.5266dupC, p.Gln1756fsX74), providing supporting evidence for a benign role. One functional assay suggests that BRCA1-H1402Y may have a reduced ability to enhance TCDD induced expression from a reporter plasmid carrying the XRE from the promoter of the CYP1A1 gene, but the activity is ~80% of WT (Kang, 2008), which may not have a major impact in vivo. Additionally, most functional assays show that its interaction with AhR is not hampered (Kang, 2008), nor is BRCA1 transciptional activation (Carvalho, 2007; Phelan, 2005; Hu, 2002) indicating neutrality. In addition, multifactorial probability models, performing systematic assessments of variants of unknown significance in the BRCA genes, which included analysis of co-occurrence in trans with known deleterious mutations, personal and family history of cancer, tumor pathology and co-segregation with disease in pedigrees, predicted this variant to be neutral (Easton_2007 and Lindor_2012). Five ClinVar submissions (evaluation after 2014) classified the variant as likely benign (3x) and benign (2x, including one expert panel-ENIGMA). Based on the evidence outlined above, the variant was classified as benign.
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000162983 SCV000803147 likely benign Hereditary cancer-predisposing syndrome 2018-05-23 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000048486 SCV001151325 likely benign not provided 2018-01-01 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000083205 SCV000115279 benign Breast-ovarian cancer, familial 1 2010-09-08 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000083205 SCV000145027 uncertain significance Breast-ovarian cancer, familial 1 1999-04-13 no assertion criteria provided clinical testing

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