Submissions for variant NM_007294.4(BRCA1):c.1911T>C (p.Thr637=)

gnomAD frequency: 0.00013  dbSNP: rs62625305

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000111731	SCV000578223	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2017-06-29	reviewed by expert panel	curation	Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/).
Invitae	RCV001083820	SCV000075649	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000168494	SCV000167245	benign	not specified	2014-02-05	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.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000111731	SCV000195896	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-11-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000162772	SCV000213249	likely benign	Hereditary cancer-predisposing syndrome	2014-07-01	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000168494	SCV000219212	benign	not specified	2017-01-18	criteria provided, single submitter	clinical testing
Counsyl	RCV000111731	SCV000220247	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-04-15	criteria provided, single submitter	literature only
Color Diagnostics, LLC DBA Color Health	RCV000162772	SCV000683001	likely benign	Hereditary cancer-predisposing syndrome	2015-07-20	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679685	SCV000806903	likely benign	not provided	2017-06-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000168494	SCV000918678	likely benign	not specified	2019-02-21	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.1911T>C alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. In vitro splicing, assessed by mini-gene assay, shows that the variant does not impact BRCA1 splicing (Anczukow_2008). The variant allele was found at a frequency of 0.0001 in 277214 control chromosomes (gnomAD and publication), predominantly at a frequency of 0.00022 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (0.00022 vs 0.001), allowing no conclusion about variant significance. c.1911T>C has been reported in the literature in individuals affected or at risk for Hereditary Breast and Ovarian Cancer (Zanella_2017, Caminsky_2016, DArgenio_2015, Borg_2010, Anczukow_2008, Judkins_2005). 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 in the UMD database (BRCA1 c.514C>T, p.Gln172X; BRCA2 c.6033_6034delTT, p.Ser2012GlnfsX5), providing supporting evidence for a benign role. Five ClinVar submissions from clinical diagnostic laboratories and reputable databases (evaluation after 2014) cite the variant as likely benign (3x) and twice as benign. Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000679685	SCV001473917	likely benign	not provided	2019-09-10	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000168494	SCV002065050	likely benign	not specified	2018-01-25	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162772	SCV002538065	likely benign	Hereditary cancer-predisposing syndrome	2021-08-25	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000168494	SCV004026797	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111731	SCV000144245	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2010-12-17	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000168494	SCV000591355	benign	not specified		no assertion criteria provided	clinical testing	This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located near a splice junction and is reported as a polymorphism in one publication (Judkins 2005). In addition, it reported to co-occur with a second pathogenic variant in 2 individuals in the UMD database.