Submissions for variant NM_007294.4(BRCA1):c.2412G>C (p.Gln804His)

gnomAD frequency: 0.00006  dbSNP: rs55746541

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000111853	SCV000244317	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 = 0.000446
Invitae	RCV001086051	SCV000075843	benign	Hereditary breast ovarian cancer syndrome	2024-01-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000590591	SCV000209938	likely benign	not provided	2020-03-13	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26381082, 18446624, 28857155, 22425665, 22366370, 16644204, 21203900, 22753008, 11183185, 16489001, 11802209, 12457999, 17924331, 21990134, 15235020, 24728327)
Ambry Genetics	RCV000162976	SCV000213464	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	RCV000111853	SCV000220696	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-09-15	criteria provided, single submitter	literature only
Color Diagnostics, LLC DBA Color Health	RCV000162976	SCV000683034	likely benign	Hereditary cancer-predisposing syndrome	2015-07-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120290	SCV000698949	benign	not specified	2021-08-19	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2412G>C (p.Gln804His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.5e-05 in 360276 control chromosomes (gnomAD and publications). This frequency is not higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (7.5e-05 vs 0.001), allowing no conclusion about variant significance. c.2412G>C has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Ellis_2000, Meindl_2002, Haffty_2005, Judkins_2005, Lalloo_2006, Wadell_2008, Tazzite_2012, Dougherty_2017, Dorling_2021) but was also reported in controls (Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Multiple co-occurrences with pathogenic variants have been reported (e.g. BRCA2 c.1310_1313delAAGA, p.Lys437IlefsX22; BRCA2 c.8167G>C, p.Asp2723His; BRCA2 c.2808_2811delACAA, p.Ala938fsX21) (Wadell_2008, Konecny_2011, Tazzite_2012; UMD and BIC databases), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Studies utilizing a multifactorial likelihood model for classification of variants which uses data such as co-occurrence with pathogenic mutations, co-segregation with disease, histopathology and immunochemical profiles of associated tumors and personal and family history of cancer, concluded the variant to be neutral (Chenevix-Trench_2006, Easton_2007, Lindor_2012). Six ClinVar submitters including an expert panel (ENIGMA) (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000111853	SCV000744657	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2015-09-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590591	SCV000888866	benign	not provided	2023-06-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000590591	SCV002049221	likely benign	not provided	2021-06-22	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120290	SCV002067701	likely benign	not specified	2018-12-04	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162976	SCV002538120	likely benign	Hereditary cancer-predisposing syndrome	2021-04-12	criteria provided, single submitter	curation
Genetics and Molecular Pathology, SA Pathology	RCV000111853	SCV002556423	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2022-05-25	criteria provided, single submitter	clinical testing	The BRCA1 c.2412G>C variant is classified as Benign
CeGaT Center for Human Genetics Tuebingen	RCV000590591	SCV004140630	likely benign	not provided	2022-10-01	criteria provided, single submitter	clinical testing	BRCA1: BP4
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120290	SCV004242833	benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003894895	SCV004714831	benign	BRCA1-related condition	2020-09-25	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).
ITMI	RCV000120290	SCV000084442	not provided	not specified	2013-09-19	no assertion provided	reference population
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111853	SCV000144422	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000590591	SCV001549418	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000120290	SCV001906160	benign	not specified		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000111853	SCV004244091	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing