ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5123C>T (p.Ala1708Val) (rs28897696)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000048803 SCV000076816 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-10-18 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.
Ambry Genetics RCV000131166 SCV000186111 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-26 criteria provided, single submitter clinical testing The p.A1708V variant (also known as c.5123C>T), located in coding exon 16 of the BRCA1 gene, results from a C to T substitution at nucleotide position 5123. The alanine at codon 1708 is replaced by valine, an amino acid with similar properties. This alteration, referred to as 5242C>T in some literature, impacts the functionally important BRCT domain and has been associated with reduced/partial BRCA1 function, suggesting that p.A1708V may act as a low or moderate disease risk allele (Lu C et al. Nat Commun. 2015 Dec;6:10086; Lee MS et al. Cancer Res. 2010 Jun;70:4880-90; Lovelock PK et al. Breast Cancer Res. 2007;9:R82). This alteration has been classified as having uncertain clinical significance by multifactorial analysis, which integrates which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, and mutation co-occurrence (Easton DF et al. Am. J. Hum. Genet. 2007 Nov;81:873-83; Lindor NM et al. Hum. Mutat. 2012 Jan;33:8-21; Vallee MP et al. Hum. Mutat. 2012 Jan;33:22-8). Based on one functional study, using saturation genome editing, this alteration does not affect the BRCA1 protein (Findlay GM et al. Nature. 2018 10;562:217-222). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence conflicting at this time, the clinical significance of this alteration remains unclear.
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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212194 SCV000494396 uncertain significance not specified 2021-04-19 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.5123C>T (p.Ala1708Val) results in a non-conservative amino acid change located in the BRCT 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 2.8e-05 in 251672 control chromosomes. Another BRCA1 missense change at the same residue p.Ala1708Glu (c.5123C>A) is a known pathogenic variant. It must be noted that while p.Ala1708Glu leads to change in amino acid charge (neutral to polar), this variant, (p.Ala1708Val) does not. c.5123C>T has been reported in the literature in individuals affected with breast and/or ovarian and other cancers (example, Chenevix-Trench_2006, Fackenthal_2012, Lovelock_2007, Caldes_2002, Pal_2015, Lu_2015, Jarhelle_2016, Moller_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. This variant was also reported in FLOSSIES database of individuals who are cancer free at the age of 70. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (BRCA2 c.5641_5644del, p.Lys1881fs) and another non-specified co-occurrence has been reported by an external laboratory in the ClinVar database, providing supporting evidence for a benign role. Multiple publications have reported experimental evidence evaluating an impact on protein function. The most pronounced variant effect leads to varied outcomes depending upon types of assays performed (example, Lovelock_2007, Lee_2008, Lu_2015, Fernandes_2019, Findlay_2018, Petitalot_2019). The variant had normal effect on protein expression and foci formation in response to DNA damage, functional homology directed repair (HDR) activity, but had conflicting results ranging from normal to intermediate/strong effect on transcription, protein folding, centrosome amplification and phosphopeptide binding. For these reasons, a recent study reports this variant among those having an intermediate impact (Petitalot_2019). The possibility of the variant to be a hypomorphic mildly causative allele associated with a late onset/variable penetrance cannot be ruled out. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Some submitters cite overlapping but not identical evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Health, Inc RCV000131166 SCV000688538 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-10 criteria provided, single submitter clinical testing This missense variant replaces alanine with valine at codon 1708 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported conflicting findings on the activity of the variant protein on various in vitro and ex vivo assays (PMID: 18036263, 20516115, 30209399, 30458859). This variant has been reported in individuals affected with personal and/or family history of breast or ovarian cancer (PMID: 15744030, 16489001, 17403394, 22034289, 26287763, 27495310) including individuals who also had a BRCA2 pathogenic co-variant (PMID: 15744030, 17403394) and in healthy controls (PMID: 15744030, 24055113, 25637381). This variant has also been reported in an individual affected with kidney renal clear cell carcinoma (PMID: 26689913). A different variant affecting the same codon (p.Ala1708Glu) is considered to be disease-causing (ClinVar variation ID: 55407), suggesting that alanine or similar amino acid at this position is important for the protein function. This variant has been identified in 8/282694 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000048803 SCV000891002 uncertain significance Hereditary breast and ovarian cancer syndrome 2021-08-04 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589633 SCV001133610 uncertain significance not provided 2019-08-15 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000031221 SCV001429075 uncertain significance Breast-ovarian cancer, familial 1 2018-07-09 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001659884 SCV001878734 uncertain significance Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
Sharing Clinical Reports Project (SCRP) RCV000031221 SCV000053821 uncertain significance Breast-ovarian cancer, familial 1 2012-05-01 no assertion criteria provided clinical testing
CSER _CC_NCGL, University of Washington RCV000148393 SCV000190092 uncertain significance Breast and/or ovarian cancer 2014-06-01 no assertion criteria provided research
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
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
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353479 SCV000591584 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Ala1708Val variant was identified in 1 of 2000 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer, and was not identified in 180 control chromosomes from healthy individuals (Dorschner 2013); however, an insufficient number of controls were included in these studies to determine the frequency of this variant in the general population. The variant was also identified in dbSNP (ID: rs28897696) “With Pathogenic, Uncertain significance allele”, NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC) database, HGMD, LOVD, the ClinVar database (classified as a uncertain significance variant by the Sharing Clinical Reports Project, derived from Myriad reports; Ambry Genetics; CSER_CC_NCGL and GeneDX), GeneInsight VariantWire database(1X, classified as “unknown significance” by a clinical laboratory) and UMD (2X as a unknown significance variant).This variant was identified in the HAPMAP-JPT in 1 of 168 chromosomes (frequency: 0.006), Exome Variant Server project in 3 of 13006 European American/African American alleles, the Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014) in 4 of 10284 chromosomes (frequency: 0.0004) from a population of African individuals, although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The p.Ala1708 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Ala1708 variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. Functional studies by Chenevix-Trench (2006) and Lee (2010) characterized the variant as unclassified with odds of 41:1 in favor of causality with strong functional effect. In addition, in the study by Lovelock (2007) this variant displayed an intermediate transcriptional transactivation activity and a normal foci formation response in response to DNA damage but induced centrosome amplification. The results of this study also raise the possibility that variant may be associated with a low or moderate risk of cancer. 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 unknown significance.
Brotman Baty Institute,University of Washington RCV000031221 SCV001242169 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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