ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3302G>A (p.Ser1101Asn) (rs41293447)

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Total submissions: 15
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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 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
Invitae RCV001082961 SCV000076148 benign Hereditary breast and ovarian cancer syndrome 2020-12-07 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: 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 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 Health, Inc 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,PreventionGenetics RCV000679691 SCV000806932 likely benign not provided 2017-07-06 criteria provided, single submitter clinical testing
Mendelics RCV000112053 SCV001140556 likely benign Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000112053 SCV001287305 uncertain significance Breast-ovarian cancer, familial 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.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112053 SCV000144706 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Sharing Clinical Reports Project (SCRP) RCV000112053 SCV000297598 likely benign Breast-ovarian cancer, familial 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.

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