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

gnomAD frequency: 0.00009  dbSNP: rs28897673

Total submissions: 24

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, 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 = 0.000000105
Labcorp Genetics (formerly Invitae), Labcorp	RCV000048083	SCV000076096	benign	Hereditary breast ovarian cancer syndrome	2025-01-30	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: seen in unaffected individuals, 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, susceptibility to, 1	2014-08-19	criteria provided, single submitter	literature only
Michigan Medical Genetics Laboratories, University of Michigan	RCV000112301	SCV000267679	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162964	SCV000683088	likely benign	Hereditary cancer-predisposing syndrome	2015-02-17	criteria provided, single submitter	clinical testing
Mendelics	RCV000112301	SCV001140638	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000112301	SCV001285180	likely benign	Breast-ovarian cancer, familial, susceptibility to, 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	RCV001811338	SCV001473492	benign	not provided	2023-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162964	SCV002538189	benign	Hereditary cancer-predisposing syndrome	2020-12-24	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000123881	SCV002760947	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001811338	SCV004033563	likely benign	not provided	2024-10-01	criteria provided, single submitter	clinical testing	BRCA1: BP1, BS3:Supporting
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492384	SCV004240259	likely benign	Breast and/or ovarian cancer	2022-10-12	criteria provided, single submitter	clinical testing
Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service	RCV004691738	SCV005196394	benign	Inherited ovarian cancer (without breast cancer)	2024-06-26	criteria provided, single submitter	clinical testing	BS3_Strong,BP1,BP5_Very Strong
Breakthrough Genomics, Breakthrough Genomics	RCV001811338	SCV005251095	benign	not provided		criteria provided, single submitter	not provided
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112301	SCV000145035	benign	Breast-ovarian cancer, familial, susceptibility to, 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.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000123881	SCV001906089	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000123881	SCV001932885	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000123881	SCV001956433	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000123881	SCV001966524	benign	not specified		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000112301	SCV004244176	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing