Submissions for variant NM_007294.4(BRCA1):c.3776A>C (p.Asn1259Thr)

dbSNP: rs483353090

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159849	SCV000209893	uncertain significance	not provided	2023-01-23	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with breast cancer (Dorling et al., 2021); Also known as 3895A>C; This variant is associated with the following publications: (PMID: 31911673, 26295337, 29884841, 32377563, 34157791, 33471991)
Invitae	RCV001084247	SCV000259957	benign	Hereditary breast ovarian cancer syndrome	2023-11-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000112181	SCV000296461	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-26	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000771318	SCV000903576	likely benign	Hereditary cancer-predisposing syndrome	2017-02-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779862	SCV000916731	uncertain significance	not specified	2018-05-21	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3776A>C (p.Asn1259Thr) results in a non-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 3.3e-05 in 245960 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (3.3e-05 vs 1.00e-03), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.3776A>C in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as benign and the other laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV000771318	SCV001182683	likely benign	Hereditary cancer-predisposing syndrome	2022-07-05	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.
Sema4, Sema4	RCV000771318	SCV002538245	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-16	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000771318	SCV003847984	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000779862	SCV004242819	likely benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112181	SCV000144876	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2013-03-25	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357117	SCV001552472	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The BRCA1 p.Asn1259Thr variant was not identified in the literature nor was it identified in the COGR, Cosmic, MutDB, LOVD 3.0, UMD-LSDB, ARUP Laboratories, or Zhejiang University databases. The variant was identified in dbSNP (ID: rs483353090) as "With Uncertain significance allele", ClinVar (classified as benign by Invitae; as uncertain significance by GeneDx and two other submiters), and in BIC (1x with unknown significance) databases. The variant was identified in control databases in 8 of 245960 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the South Asian population in 8 of 30782 chromosomes (freq: 0.0003), while the variant was not observed in the African, Other, Latino, European, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Asn1259 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.