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

gnomAD frequency: 0.00011  dbSNP: rs80357250

Total submissions: 21

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, 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 = 0.000194
Invitae	RCV000195313	SCV000075691	benign	Hereditary breast ovarian cancer syndrome	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000679687	SCV000209934	likely benign	not provided	2020-08-31	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24607278, 22753008, 28398198, 21990134, 24448499, 23867111, 24504028)
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: 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.
Eurofins Ntd Llc (ga)	RCV000679687	SCV000224992	uncertain significance	not provided	2014-09-04	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679687	SCV000806907	likely benign	not provided	2017-12-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	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	2023-09-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000031022	SCV001140588	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001723592	SCV002067553	uncertain significance	not specified	2018-10-22	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162815	SCV002538083	likely benign	Hereditary cancer-predisposing syndrome	2020-11-09	criteria provided, single submitter	curation
Revvity Omics, Revvity	RCV000679687	SCV003830132	uncertain significance	not provided	2021-10-28	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000735491	SCV003838245	likely benign	Breast and/or ovarian cancer	2022-03-16	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001723592	SCV004026794	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031022	SCV000053615	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2008-12-15	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031022	SCV000144272	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
CSER _CC_NCGL, University of Washington	RCV000195313	SCV000503555	uncertain significance	Hereditary breast 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
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001723592	SCV001953729	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001723592	SCV001971454	benign	not specified		no assertion criteria provided	clinical testing