Submissions for variant NM_007294.4(BRCA1):c.1534C>T (p.Leu512Phe)

gnomAD frequency: 0.00006  dbSNP: rs41286294

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031001	SCV001161487	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-06-18	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 = 0.000143
Labcorp Genetics (formerly Invitae), Labcorp	RCV001084962	SCV000075530	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131272	SCV000186240	likely benign	Hereditary cancer-predisposing syndrome	2020-04-07	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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	RCV000047517	SCV000209929	likely benign	not specified	2017-04-18	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.
Eurofins Ntd Llc (ga)	RCV000724518	SCV000224997	uncertain significance	not provided	2015-01-07	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000724518	SCV000296346	likely benign	not provided	2023-05-15	criteria provided, single submitter	clinical testing
Counsyl	RCV000031001	SCV000488220	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2016-09-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000047517	SCV000698872	benign	not specified	2022-05-16	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.1534C>T (p.Leu512Phe) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251232 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1534C>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (examples- Meindl_2002, Judkins_2005, Jimenez_2009, Plascocinska_2016). These data do not allow any conclusion about variant significance. Co-occurrences with other pathogenic variants have been reported [BRCA1 c.81_4986del , p.Cys27X; BRCA2 c.8023A>G , p.Ile2675Val; and BRCA2 c.5909C>A, p.Ser1970X (BIC database); BRCA1 c.1570delG, p.Ala524Glnfs (Jimenez_2009); BRCA2 c.1813dupA, p.Ile605AsnfsX11 (internal sample)], providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten ClinVar submitters (evaluation after 2014) reported the variant with conflicting assessments, citing the variant as uncertain significance (n=2), likely benign (n=7), and benign (n=1, expert panel). Based on the evidence outlined above, the variant was classified as benign.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001084962	SCV000891037	likely benign	Hereditary breast ovarian cancer syndrome	2021-08-26	criteria provided, single submitter	clinical testing	The BRCA1 c.1534C>T (p.Leu512Phe) missense change has a maximum subpopulation frequency of 0.0078% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/17-41246014-G-A). Six of seven in silico tools predict a deleterious effect of this variant on protein function (PP3), however in vitro functional studies have shown that this variant results in an activity comparable to the wild type in homology-directed DNA repair (HDR) assays (BS3; PMID: 32546644). This variant has been reported in an individual with uterine serous carcinoma (PMID: 22811390) and an individual in a family with two or more cases of breast cancer diagnosed after 50 years of age (PMID: 11802209). In addition, this variant has been reported in three women older than 70 years of age who have never had cancer (BS2_supporting; https://whi.color.com/variant/17-41246014-G-A). This variant has been reported to co-occur with pathogenic variants in BRCA1 and BRCA2 (BP2; UMD database). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria: PP3, BS3, BS2_supporting, BP2.
Color Diagnostics, LLC DBA Color Health	RCV000131272	SCV000902901	likely benign	Hereditary cancer-predisposing syndrome	2016-01-14	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000047517	SCV002068133	likely benign	not specified	2020-05-04	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000047517	SCV002760942	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000031001	SCV004818309	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-12-13	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000724518	SCV005093099	benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	BRCA1: BP1, BP2, BS3:Supporting, BS2
Sharing Clinical Reports Project (SCRP)	RCV000031001	SCV000053593	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2012-07-05	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031001	SCV000144128	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2003-12-23	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355803	SCV001550791	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Leu512Phe variant was identified in 4 of 2744 proband chromosomes (frequency: 0.001) from German, American and British individuals or families with HBOC or endometrial cancer (Meindl_2002_11802209, Pennington_2012_22811390, Plaskocinska_2016_27208206). The variant was also identified in dbSNP (ID: rs41286294) “With Uncertain significance, other allele”, ClinVar (classified with conflicting interpretations of pathogenicity; submitters: likely benign by GeneDx, Invitae and SCRP; and uncertain significance by Ambry Genetics, EGL Genetic Diagnostics (Eurofins Clinical Diagnostics), Quest Diagnostics Nichols Institute San Juan Capistrano, Counsyl and BIC ), Clinvitae (5x), Genesight-COGR (1x), LOVD 3.0 (1x ), UMD-LSDB (9x as class 2 - likely neutral, co-occurring with pathogenic BRCA2 variants (c.8023A>G, p.Ile2675Val and c.5909C>A, p.Ser1970X)), and BIC Database (6x with unknown clinical importance, classification pending); and was not identified in Cosmic, MutDB, ARUP Laboratories, or Zhejiang Colon Cancer Database. The variant was identified in control databases in 11 of 276590 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European Non-Finnish in 11 of 126252 chromosomes (freq: 0.00009), while not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Leu512Phe residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004554613	SCV004738062	likely benign	BRCA1-related disorder	2023-05-02	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).