ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2002C>T (p.Leu668Phe) (rs80357250)

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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) RCV000031022 SCV000244312 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 = 0.000194
Invitae RCV000195313 SCV000075691 benign Hereditary breast and ovarian cancer syndrome 2020-12-02 criteria provided, single submitter clinical testing
GeneDx RCV000047678 SCV000209934 likely benign not specified 2018-02-13 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 RCV000162815 SCV000213298 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000679687 SCV000224992 uncertain significance not provided 2014-09-04 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000679687 SCV000806907 likely benign not provided 2017-12-06 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162815 SCV000910707 benign Hereditary cancer-predisposing syndrome 2017-02-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000679687 SCV001133510 benign not provided 2018-12-06 criteria provided, single submitter clinical testing
Mendelics RCV000031022 SCV001140588 likely benign Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031022 SCV000053615 benign Breast-ovarian cancer, familial 1 2008-12-15 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031022 SCV000144272 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
CSER _CC_NCGL, University of Washington RCV000195313 SCV000503555 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-08-01 no assertion criteria provided research Found in a male patient having exome sequencing for an unrelated indication. No known personal or family history of breast cancer.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353403 SCV000591362 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The p.Leu668Phe variant was identified in 11 of 3508 proband chromosomes (frequency: 0.003) from individuals with breast or ovarian cancer and was identified in 3 of 2748 healthy control chromosomes (frequency: 0.001) from these studies (Cvok 2008, Diez 2003, Infante 2006, Osorio 2007, Shattuck-Eidens 1997). The variant was also reported in the following databases: dbSNP (ID: rs80357250) “With non-pathogenic allele”, UMD (2X as an unclassified variant), BIC (25X with unknown clinical importance), and LOVD. The p.Leu668 residue is conserved in mammals; however, computational analyses (PolyPhen2, SIFT, AlignGVGD, BLOSUM) provide inconsistent predictions regarding the impact of the p.Leu668Phe variant to the protein and this information is not very predictive of pathogenicity. In silico studies have either predicted this variant as neutral or close to the neutral threshold (Abkevich 2004, Easton 2007, Lindor 2012, Tavtigian 2006) and Myriad classifies this variant as a polymorphism (personal communication). 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.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735491 SCV000863629 likely benign Breast and/or ovarian cancer 2013-06-14 no assertion criteria provided clinical testing

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