ClinVar Miner

Submissions for variant NM_007300.4(BRCA1):c.2351C>T (p.Ser784Leu) (rs55914168)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000203625 SCV000075822 likely benign Hereditary breast and ovarian cancer syndrome 2017-12-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131345 SCV000186320 likely benign Hereditary cancer-predisposing syndrome 2018-04-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other data supporting benign classification
GeneDx RCV000587427 SCV000210129 uncertain significance not provided 2018-03-22 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.2351C>T at the cDNA level, p.Ser784Leu (S784L) at the protein level, and results in the change of a Serine to a Leucine (TCG>TTG). This variant, also denoted 2470C>T using alternate nomenclature, was observed in an individual with a personal and/or family history of breast and/or ovarian cancer (van der Hout 2006) as well as in 2/140 Latina women with breast cancer and a family history of breast and/or ovarian cancer, but was absent in 48 cancer-free Latina controls (McKean-Cowdin 2005). This variant was suggested to be benign based on functional analyses by Loke et al. (2015) which interrogated binding to multiple BRCA1 binding partners and DNA damage response. BRCA1 Ser784Leu was observed at an allele frequency of 0.12% (40/33556) in individuals of Latino ancestry in large population cohorts (Lek 2016). BRCA1 Ser784Leu is located in the DNA binding domain and a region known to interact with multiple other proteins (Narod 2004, Paul 2014). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA1 Ser784Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000031045 SCV000487970 uncertain significance Breast-ovarian cancer, familial 1 2015-12-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587427 SCV000698944 likely benign not provided 2017-03-30 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.2351C>T (p.Ser784Leu) variant causes a missense change involving the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant. These in silico predictions have not been verified or disputed with functional studies, with one study classifying the variant as benign based on the presence of homozygotes and using it in a control group (Loke_Hum Mol Genet_2015).The variant of interest has been found in a large, broad control population, ExAC in 20/121540 control chromosomes, predominantly observed in the Latino subpopulation at a frequency of 0.001642 (19/11572). This frequency is about 2 times the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005), suggesting this is likely a benign polymorphism found primarily in the populations of Latino origin. The variant has been reported in affected individuals in the literature without strong evidence for causality (co-occurrence and co-segregation data). Co-occurrence of this variant and a likely pathogenic variant (BRCA1 c.942_956delinsCTTACTTC; p.Arg315fsX24) has been reported in an internal specimen. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign. Taken together, this variant is classified as likely benign.
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000031045 SCV000743416 uncertain significance Breast-ovarian cancer, familial 1 2014-10-08 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000031045 SCV000744660 uncertain significance Breast-ovarian cancer, familial 1 2015-09-21 criteria provided, single submitter clinical testing
Color RCV000131345 SCV000902866 likely benign Hereditary cancer-predisposing syndrome 2016-02-22 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031045 SCV000053639 likely benign Breast-ovarian cancer, familial 1 2009-08-28 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031045 SCV000144388 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing

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