Submissions for variant NM_007294.4(BRCA1):c.154C>T (p.Leu52Phe)

gnomAD frequency: 0.00001  dbSNP: rs80357084

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001085660	SCV000075532	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000164750	SCV000215424	likely benign	Hereditary cancer-predisposing syndrome	2021-02-24	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	RCV000588129	SCV000293475	uncertain significance	not provided	2022-12-02	criteria provided, single submitter	clinical testing	Observed in individuals with personal history of breast and/or ovarian cancer, but also in healthy controls (Han 2006, Kim 2006, Sugano 2008, Jang 2012, Hirotsu 2015, Nakamura 2015, Yoon 2017, Hwang 2017, Ryu 2017, Choi 2018, Li 2019, Kim 2020, Momozawa 2021); Published functional studies are conflicting: BARD1 binding, single-stranded DNA repair activity, and cell survival similar to wild-type, mixed results with respect to homology-directed repair and E3 ubiquitin ligase activity, decreased E2 binding, and intermediate increase in centrosome amplification (Brzovic 2003, Morris 2006, Ransburgh 2010, Kais 2012, Towler 2013, Starita 2015, Findlay 2018, Starita 2018, Kweon 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 273C>T; This variant is associated with the following publications: (PMID: 23161852, 17100994, 20967475, 22217648, 26709275, 28111427, 32803532, 21725363, 12732733, 20103620, 19016756, 16949048, 25802882, 27658390, 24249303, 18528753, 25823446, 28392550, 28364669, 21309043, 11573085, 28440963, 25186627, 15385441, 16267036, 29020732, 29215753, 18493658, 28970858, 29176636, 29731985, 30209399, 30415210, 30725392, 31131967, 30866919, 29240602, 31467430, 29752822, 32548945, 31924417, 32973888, 31907386, 32741062, 32377563, 33606355, Paquette[article]2021, 24389207, 20104584, 8944023, 33720123, 32467295, 30287823, 33428613, 33875706, 30219179, 35373174, 16403807)
Counsyl	RCV000031002	SCV000487928	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2015-12-22	criteria provided, single submitter	clinical testing
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	RCV000236664	SCV000586865	likely benign	not specified	2017-04-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164750	SCV000682971	likely benign	Hereditary cancer-predisposing syndrome	2020-11-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000236664	SCV000698873	benign	not specified	2021-02-21	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.154C>T (p.Leu52Phe) results in a non-conservative amino acid change located in the Zinc finger, RING-type domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00065 in 299432 control chromosomes, predominantly at a frequency of 0.0014 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.154C>T has been reported in the literature predominantly from East Asian cohorts of individuals affected with Breast and/or Ovarian Cancer (example, Sugano_2008, Han_2006, Jang_2012, Kim_2006, Judkins_2005, Eoh_2017, Yoon_2016, Park_2017, Momozawa_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (BRCA2 c.5645C>A , p.Ser1882X), providing supporting evidence for a benign role. Several publications report experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on protein expression, HDR activity, or BARD1 binding (example, Yoon_2017, Starita_2015, Ransburgh_2010, Findlay_2018). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2; VUS, n=6). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the lack of any evidence supporting an actionable outcome spanning at-least 12 years of cross sectional review, supported by multiple reports of a neutral functional impact and at-least one co-occurrence as outlined above, the variant was classified as benign.
Illumina Laboratory Services, Illumina	RCV000031002	SCV001287535	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 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 Center, Key Laboratory of Carcinogenesis and Translational Research	RCV001085660	SCV001430328	uncertain significance	Hereditary breast ovarian cancer syndrome	2020-05-01	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798025	SCV002043425	uncertain significance	Breast and/or ovarian cancer	2021-04-23	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000236664	SCV002046088	benign	not specified	2021-01-05	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000164750	SCV002538040	likely benign	Hereditary cancer-predisposing syndrome	2020-12-02	criteria provided, single submitter	curation
Revvity Omics, Revvity	RCV000588129	SCV003830131	uncertain significance	not provided	2022-01-04	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031002	SCV000053594	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2012-12-11	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031002	SCV000144495	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-02-20	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000031002	SCV000591244	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing	The p.Leu52Phe variant has been identified in 11 out of 3896 proband chromosomes (frequency 0.003) from individuals with breast and ovarian cancers, and was not identified in 668 control chromosomes (Kim 2006, Han 2006, Sugano 2008 ), increasing the likelihood this variant may have clinical significance. However, it should be noted that this individual was indicated as Asian, and our lab has sequenced the BRCA1 gene in a limited number of individuals from this background such that the full spectrum of benign variation may not yet been defined for this gene in this population and increasing the possibility that this may be a benign variant. It is listed in the dbSNP database as coming from a "clinical source" (ID#: rs80357084) with no frequency information available, and so the frequency of this variant in the general population is not known. The p.Leu52 is conserved in mammals and other species and in-silico or computational analyses (PolyPhen2, SIFT, AlignGVGD) suggest that this variant may impact protein function, however this is not predictive enough to assume pathogenicity. Several in vitro studies suggested modest to no effect regarding the role of this variant in centrosome duplication, binding to BARD1, and ubiquitination activity (Brzovic 2003, Morris 2006, Ransburgh 2010, Sarkar 2008, Katoh 2005, Kais 2012, Atipairin 2011). In summary, based on current information presented above, we cannot rule out the possibility that this variant may have clinical significance, but this variant is classified as VUS.
Brotman Baty Institute, University of Washington	RCV000031002	SCV001241594	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153309	SCV003843621	likely pathogenic	Ovarian cancer	2022-01-01	flagged submission	clinical testing
BRCAlab, Lund University	RCV000031002	SCV004244188	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing