ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5411T>A (p.Val1804Asp) (rs80356920)

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Total submissions: 14
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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) RCV000112647 SCV000244402 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 = 0.0000374
Invitae RCV001086725 SCV000076995 benign Hereditary breast and ovarian cancer syndrome 2020-12-08 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000148405 SCV000190104 uncertain significance Ovarian cancer 2014-06-01 criteria provided, single submitter research Low GERP score may suggest that this variant may belong in a lower pathogenicity class
GeneDx RCV000120302 SCV000209992 likely benign not specified 2017-10-23 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 RCV000162993 SCV000213481 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.
Color Health, Inc RCV000162993 SCV000683311 likely benign Hereditary cancer-predisposing syndrome 2015-04-02 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000679701 SCV000806973 likely benign not provided 2017-01-17 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000679701 SCV000887729 benign not provided 2018-10-30 criteria provided, single submitter clinical testing
Mendelics RCV000112647 SCV001140467 likely benign Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
ITMI RCV000120302 SCV000084454 not provided not specified 2013-09-19 no assertion provided reference population
Breast Cancer Information Core (BIC) (BRCA1) RCV000112647 SCV000145504 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Sharing Clinical Reports Project (SCRP) RCV000112647 SCV000189348 benign Breast-ovarian cancer, familial 1 2011-03-01 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353560 SCV000591630 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Val1804Asp variant was identified in 2 of 1268 proband chromosomes (frequency: 0.002) from individuals with breast or ovarian cancer (Diez 2003), and was also identified in 2 of 2108 control chromosomes (frequency 0.001) from another study (Osorio 2007). This variant was reported in dbSNP (rs80356920) “with untested allele”, in LOVD, and in BIC 14X with unknown clinical importance. The p.Val1804Asp variant was also identified in UMD 6X as a neutral variant, where it was reported to have co-occurred with two different known BRCA1 pathogenic mutations (BRCA1 c.5266dup (p.Gln1756ProfsX74); BRCA1 c.2269delG (p.Val757PhefsX8)), increasing the likelihood that it is benign. The results of functional studies in the literature are somewhat conflicting, though most lean toward neutrality. Ostrow (2004) determined that the variant reduced transcriptional activity in a yeast-based assay, suggesting it may be deleterious; Carvalho (2007) found transcription activity comparable to wild type in yeast but reduced in mammalian cells, suggesting that it may represent a moderate-risk variant; while Lee (2010) found no functional impact of the variant on transcription. Two studies determined that the variant had no impact on protease sensitivity, and no destabilizing effect on the BRCT domain), suggesting that it is neutral (Lee 2010 20516115, Williams 2003 14534301. In addition, histopathology results provide evidence for neutrality, with loss of the variant allele in tumour tissue (Spearman 2008 18824701). Furthermore, the p.Val1804 residue is poorly conserved in mammals and lower organisms; computational analyses (PolyPhen2, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein; and in silico structural or probability-based models suggest that this is a neutral variant (Capanu 2011, Easton 2007, Lindor 2012, Mirkovic 2004). 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 predicted benign.
Brotman Baty Institute,University of Washington RCV000112647 SCV001238353 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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