Submissions for variant NM_007294.4(BRCA1):c.3302G>A (p.Ser1101Asn)

gnomAD frequency: 0.00064  dbSNP: rs41293447

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112053	SCV000244338	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 = 0.00000000632
Labcorp Genetics (formerly Invitae), Labcorp	RCV001082961	SCV000076148	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131159	SCV000186102	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.
GeneDx	RCV000048135	SCV000209951	benign	not specified	2016-07-21	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000048135	SCV000219227	likely benign	not specified	2017-01-18	criteria provided, single submitter	clinical testing
Counsyl	RCV000112053	SCV000220332	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-05-20	criteria provided, single submitter	literature only
Vantari Genetics	RCV000131159	SCV000267006	likely benign	Hereditary cancer-predisposing syndrome	2015-12-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131159	SCV000683097	benign	Hereditary cancer-predisposing syndrome	2014-12-16	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000131159	SCV000803149	likely benign	Hereditary cancer-predisposing syndrome	2018-05-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679691	SCV000806932	likely benign	not provided	2017-07-06	criteria provided, single submitter	clinical testing
Mendelics	RCV000112053	SCV001140556	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000112053	SCV001287305	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2017-04-27	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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Sema4, Sema4	RCV000131159	SCV002538197	benign	Hereditary cancer-predisposing syndrome	2021-12-23	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000679691	SCV002545929	benign	not provided	2022-04-01	criteria provided, single submitter	clinical testing	BRCA1: BP1, BP4, BS3:Moderate, BS1
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000048135	SCV002760937	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000112053	SCV004016795	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-07-07	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112053	SCV000144706	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000112053	SCV000297598	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2008-11-26	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000048135	SCV000591435	benign	not specified		no assertion criteria provided	clinical testing	The p.Ser1101Asn variant has been reported in 4 of 6852 proband chromosomes in individuals with breast or ovarian cancers (Alsop_2012_22711857, Borg_2010_20104584, Stegel_2011_21232165) and was absent in 80 control chromosomes from these studies. This variant was also identified in the UMD database 20x as a neutral variant and was reported as co-occuring with other pathogenic variants including: BRCA1 c.1386delG (p.Thr464ProfsX11), BRCA2 c.673_676delACTA (p.Thr225LeufsX4), BRCA2 c.1440_1441delCA (p.Ile481SerfsX32), increasing the likelihood the p.Ser1101Asn variant does not have clinical significance. p.Ser1101Asn was also identified in the BIC database (14x of unknown clinical importance) and in the exome variant server in 2 of 8600 european chromosomes (frequency: 0.0002) increasing the likelihood this is a low frequency benign variant in certain populations of origin. The p.Ser1101 residue is not conserved in all mammals or lower species and computational analyses (PolyPhen2, SIFT, AlignGVGD, BLOSUM) provide inconsistent predictions regarding the impact to the protein but this information is not very predictive of pathogenicity. Furthermore, a number of in-silico functional studies suggest this variant is predicted neutral or has no effect (Abkevich_2004_15235020, Burk-Herrick_2005_16518693, Easton_2007_17924331, Lindor_2012_21990134), while others suggest the variant may be of uncertain clinical significance, (Judkins_2005_16267036, Lee_2007_18284688). This variant occurs outside of the splicing consensus sequence but in-silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicts a greater than 10% difference in splicing in 4 of 5 different programs. However, the prediction is abolishment of a splicing donor site for a nucleotide residue that occurs 795 bp from the known splices consensus site for exon 11. Thus, this finding is not likely to have functional or clinical significance. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000048135	SCV001799394	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000048135	SCV001906449	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000048135	SCV001928409	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000048135	SCV001955521	benign	not specified		no assertion criteria provided	clinical testing