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

gnomAD frequency: 0.00001  dbSNP: rs80357365

Total submissions: 14

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, 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 = 0.000187
Invitae	RCV001087632	SCV000076499	benign	Hereditary breast ovarian cancer syndrome	2024-01-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000048486	SCV000209970	likely benign	not provided	2018-08-27	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 21702907, 17924331, 15689452, 21990134, 17308087, 12080089, 15235020, 22753008, 16267036, 18992264, 11748305)
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, susceptibility to, 1	2014-09-18	criteria provided, single submitter	literature only
Color Diagnostics, LLC DBA Color Health	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 Center for Human Genetics Tuebingen	RCV000048486	SCV001151325	likely benign	not provided	2018-01-01	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000254639	SCV004026766	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000048486	SCV004564274	likely benign	not provided	2022-12-28	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003894898	SCV004715855	benign	BRCA1-related condition	2020-10-04	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Sharing Clinical Reports Project (SCRP)	RCV000083205	SCV000115279	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2010-09-08	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000083205	SCV000145027	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	1999-04-13	no assertion criteria provided	clinical testing