ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5123C>T (p.Ala1708Val) (rs28897696)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131166 SCV000186111 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Conflicting evidence
CSER_CC_NCGL; University of Washington Medical Center RCV000148393 SCV000190092 uncertain significance Breast and/or ovarian cancer 2014-06-01 no assertion criteria provided research
Clinical Genomics Lab,St. Jude Children's Research Hospital RCV000761087 SCV000891002 uncertain significance Craniopharyngioma 2016-11-15 no assertion criteria provided clinical testing
Color RCV000131166 SCV000688538 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-30 criteria provided, single submitter clinical testing
Department of Medical Genetics,University Hospital of North Norway RCV000031221 SCV000301438 uncertain significance Breast-ovarian cancer, familial 1 2016-05-01 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000048803 SCV000591584 uncertain significance Hereditary breast and ovarian cancer syndrome 2015-03-27 criteria provided, single submitter clinical testing
GeneDx RCV000589633 SCV000210201 uncertain significance not provided 2017-12-06 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5123C>T at the cDNA level, p.Ala1708Val (A1708V) at the protein level, and results in the change of an Alanine to a Valine (GCG>GTG). Using alternate nomenclature, this variant has been previously published as BRCA1 5242C>T. BRCA1 Ala1708Val has been observed in several individuals with a personal and/or family history of breast cancer and in an individual with renal cancer (Chenevix-Trench 2006, Fackenthal 2012, Lu 2015, Pal 2015), but was also present in large cohorts of control individuals undergoing whole exome sequencing (Dorschner 2013, Amendola 2015). In vitro functional studies have reported mixed results for BRCA1 Ala1708Val. Although some studies demonstrate a severe folding defect, compromised binding activity and specificity, diminished homologous recombination repair activity, and decreased transcriptional activation as compared to wild type, others have reported intermediate transcriptional activation and normal foci formation in response to DNA damage (Lovelock 2007, Lee 2010, Lu 2015). Lovelock et al. (2007) suggest that BRCA1 Ala1708Val may represent a pathogenic variant with reduced penetrance. BRCA1 Ala1708Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). BRCA1 Ala1708Val is located in the BRCT 1 domain and a region known to interact with multiple other proteins (UniProt, Paul 2014) . In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether BRCA1 Ala1708Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000048803 SCV000494396 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-05-16 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.5123C>T (p.Ala1708Val) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 3/120986 control chromosomes at a frequency of 0.0000248, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). One co-occurrence of this variant and a pathogenic variant (ATM c.7271T>G/p.Val2424Gly) has been reported in one family (http://www.kconfab.org/Progress/Mutations.aspx). On the other hand, multiple studies showed this variant significantly affected BRCA1 function. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as Uncertain significance. Taken together, this variant is classified as VUS.
Integrated Genetics/Laboratory Corporation of America RCV000589633 SCV000699206 uncertain significance not provided 2017-06-12 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.5123C>T (p.Ala1708Val) variant involves the alteration of a conserved nucleotide, is located in BRCT domain of the protein (InterPro) and is predicted to be damaging by 5/5 in silico tools. This variant was found in 4/120986 control chromosomes (including ExAC), predominantly observed in the African subpopulation at a frequency of 0.000389 (4/10284). This frequency is lower than the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). This variant has been reported in several HBOC patients without strong evidence for or against pathogenicity. One co-occurrence of this variant and a pathogenic variant (ATM c.7271T>G/p.Val2424Gly) has been reported in one family (http://www.kconfab.org/Progress/Mutations.aspx). Functional studies showed that this variant leads to varied effects depending upon types of assays performed (Lovelock_2007, Lee_2008, Lu_2015). The variant had normal effect on protein expression and foci formation in response to DNA damage but had intermediate to strong effect on transcription, protein folding, centrosome amplification and phosphopeptide binding. The possibility of the vaiant to be a mild causative mutation associated with a late onset of the disease. Another missense change at the same residue A1708E is a known pathogenic variant; while A1708E leads to charge change, A1708V does not. Multiple clinical diagnostic laboratories/reputable databases (via ClinVar) have classified this variant as uncertain significance. This variant has been observed in our lab in patients with a personal and/or family history of breast/ovarian cancer, however no segregation data are available for analysis. According to ACMG criteria, rules PS3, PM1, PM5, PP2, PP3 would all apply. Taken together, this variant is currently classified as VUS-Possibly pathogenic until additional clinical data becomes available.
Invitae RCV000048803 SCV000076816 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 1708 of the BRCA1 protein (p.Ala1708Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs28897696, ExAC 0.04%). This variant has been reported in individuals with a personal and/or family history of breast cancer (PMID: 16489001, 18036263, 22034289, 26287763, 27495310), and an individual affected with kidney cancer (PMID: 26689913). In addition, it has been found in an individual with ovarian cancer (Invitae). However, in that individual a pathogenic allele was also identified in BRCA2, which suggests that this c.5123C>T variant was not the primary cause of disease. This variant is also known as 5242C>T (A1708V) in the literature. ClinVar contains an entry for this variant (Variation ID: 37640). Experimental studies have shown conflicting results for the effect of this missense change on BRCA1 structure and function. This variant caused decreased stability and compromised transcriptional activation, phosphopeptide binding (PMID: 20516115), and homology-directed repair activity (PMID: 26689913). However, in a different study, a protein with this missense variant showed normal stability and a relatively smaller decrease in transcriptional activity (PMID: 18036263). Additionally, a study utilizing a saturation genome editing (SGE) method has reported that this variant does not substantially affect BRCA1 protein function (PMID: 30209399). A different missense substitution at this codon (p.Ala1708Glu) has been determined to be pathogenic (PMID: 1157798, 11802208, 15923272, 19404736, 23867111). This suggests that the alanine residue is critical for BRCA1 protein function and that other missense substitutions at this position may also be pathogenic. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000212194 SCV000587467 uncertain significance not specified 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000031221 SCV000053821 uncertain significance Breast-ovarian cancer, familial 1 2012-05-01 no assertion criteria provided clinical testing

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