Submissions for variant NM_007294.4(BRCA1):c.4342A>G (p.Ser1448Gly)

gnomAD frequency: 0.00001  dbSNP: rs80357486

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001084944	SCV000076542	likely benign	Hereditary breast ovarian cancer syndrome	2023-12-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000165183	SCV000215895	benign	Hereditary cancer-predisposing syndrome	2015-05-07	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	RCV000083207	SCV000488379	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2016-03-10	criteria provided, single submitter	clinical testing
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center	RCV000414754	SCV000492487	uncertain significance	Breast neoplasm		criteria provided, single submitter	research
GeneDx	RCV000587513	SCV000518441	likely benign	not provided	2018-04-13	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27403073, 31954625, 24884479, 23867111, 25682074, 23704879)
Genetic Services Laboratory, University of Chicago	RCV000420110	SCV000593677	uncertain significance	not specified	2016-10-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587513	SCV000699133	uncertain significance	not provided	2016-07-15	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.4342A>G (p.Ser1448Gly) variant involves the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a benign outcome (SNPs&GO not captured due to low reliability index). Ser1448 is not highly conserved in vertebrates and is not located in a known functional domain of the Breast cancer type 1 susceptibility protein. Multiple assays have shown that this variant has no impact on function, including a Cisplatin (anticancer drug) sensitivity assay, transcription activation assay, and the ability to support growth proliferation in deficient embryonic stem cells (Bouwman_Cancer Discovery_2013 and Woods_GenomicMed_2016). This variant was found in 2/121452 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). The variant has been reported in 3 breast/ovarian cancer patients in the literature without evidence of causality (i.e co-segregation studies). One patient reported in the UMD database carried a pathogenic BRCA2 co-occurrence, c.3545_3546delTT (p.Phe1182X). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as either Benign (without evidence to independently evaluate) or a VUS. Taken together, this variant is classified as a VUS-possibly benign until additional information is available.
Color Diagnostics, LLC DBA Color Health	RCV000165183	SCV000903267	benign	Hereditary cancer-predisposing syndrome	2016-05-16	criteria provided, single submitter	clinical testing
Mendelics	RCV000083207	SCV001140528	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000083207	SCV000115281	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2012-03-29	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000083207	SCV000145062	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-11-25	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000587513	SCV001929275	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000587513	SCV001952730	likely benign	not provided		no assertion criteria provided	clinical testing