ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4868C>G (p.Ala1623Gly) (rs80356862)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000048680 SCV000076693 likely pathogenic Hereditary breast and ovarian cancer syndrome 2020-09-25 criteria provided, single submitter clinical testing This sequence change replaces alanine with glycine at codon 1623 of the BRCA1 protein (p.Ala1623Gly). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and glycine. This variant is present in population databases (rs80356862, ExAC 0.009%). This variant has been reported in individuals affected with breast and ovarian cancer (PMID: 26681312, 23210696, 12491499, 22711857, 18312450, 27208206). This variant is also known as 4987C>G in the literature. ClinVar contains an entry for this variant (Variation ID: 37614). A multifactorial likelihood analysis based on genetic evidence such as family history, co-segregation with disease, and co-occurrence with pathogenic variants predicts that this variant is likely deleterious (PMID: 17924331). Experimental studies have shown that this variant alters RNA splicing, resulting in a 119 nucleotide deletion that leads to a truncated BRCA1 protein (PMID: 20513136, 27273131). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx RCV000074598 SCV000108683 likely pathogenic not provided 2021-03-23 criteria provided, single submitter clinical testing Observed in individuals with personal or family history of BRCA1-related cancers, segregating with disease in at least one family (Adem 2003, Evans 2008, Alsop 2012, Chiang 2012, Senter 2014, Plaskocinska 2016, Delgado-Balderas 2018); Published studies demonstrate a damaging effect on splicing: results in a deletion of 119 nucleotides leading to a frameshift (Walker 2010, Byers 2016, Wai 2020); Multifactorial studies report 31:1 odds in favor of causality (Easton 2007); Not observed at a significant frequency in large population cohorts (Lek 2016); While protein-based in silico analysis supports that this missense variant does not alter protein structure/function, splice predictors support a deleterious effect; Also known as 4987C>G; This variant is associated with the following publications: (PMID: 12491499, 25782689, 20513136, 30646163, 29922827, 30212499, 17924331, 22711857, 23210696, 26913838, 27273131, 26681312, 18312450, 23725378, 26052229, 20167696, 28781887, 27208206, 29997359, 29936257, 28726806, 28152038, 29446198, 30322717, 30765603, 31911673, 32123317, 31409081, 31447099, 32322110, 33087888)
Ambry Genetics RCV000131686 SCV000186722 pathogenic Hereditary cancer-predisposing syndrome 2018-04-25 criteria provided, single submitter clinical testing The c.4868C>G pathogenic mutation (also known as p.A1623G), located in coding exon 14 of the BRCA1 gene, results from a C to G substitution at nucleotide position 4868. The alanine at codon 1623 is replaced by glycine, an amino acid with similar properties. This mutation has been reported in individuals with hereditary breast and/or ovarian cancer (Chiang HC et al. Exp. Hematol. Oncol. 2012 Oct;1:31; Alsop K et al. J. Clin. Oncol. 2012 Jul;30:2654-63; Walker LC et al. Hum. Mutat. 2010 Jun;31:E1484-505; Byers H et al. Eur. J. Hum. Genet. 2016 11;24(11):1591-1597). RT-PCR analyses in vitro and RNA analyses on patient samples have shown that this alteration aberrantly affects splicing, causing a truncated protein subject to nonsense mediated decay (Ambry internal data; Walker LC et al. Hum. Mutat. 2010 Jun;31:E1484-505; Byers H et al. Eur. J. Hum. Genet. 2016 11;24(11):1591-1597). Of note, this alteration is also designated as 4987C>G in published literature. Based on the available evidence, this alteration is classified as a pathogenic mutation.
Counsyl RCV000031195 SCV000221119 likely pathogenic Breast-ovarian cancer, familial 1 2015-02-05 criteria provided, single submitter literature only
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031195 SCV000326053 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency RCV000048680 SCV000586903 pathogenic Hereditary breast and ovarian cancer syndrome 2017-04-18 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000074598 SCV000605895 pathogenic not provided 2015-07-23 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131686 SCV000683223 likely pathogenic Hereditary cancer-predisposing syndrome 2019-12-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000048680 SCV000699180 pathogenic Hereditary breast and ovarian cancer syndrome 2020-07-06 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4868C>G (p.Ala1623Gly) results in a non-conservative amino acid change located in the breast cancer cluster region (BCCR) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. However, several computational tools predict a significant impact on normal splicing: four predict the variant creates a cryptic exonic 5' donor site. This prediction has been confirmed by studies using patient derived lymphocyte mRNA that has demonstrated the variant to result in a 119 bp deletion from exon 16, leading to a truncated protein (Walker 2010, Byers 2016) (ACMG PS3). The variant had an incomplete effect on splicing, as the full length product coding for the missense protein was also detected, although in a minor fraction of the transcripts (Walker 2010). The variant allele was found at a frequency of 4.0e-06 in 251384 control chromosomes (gnomAD exomes) indicating that this is a rare variant (ACMG PM2). c.4868C>G has been reported in the literature in several affected individuals from unrelated families with a history of early onset breast and/or ovarian cancer (ranging from 39-59 in our ascertainment) (example, Adem 2002, Evans 2008, Alsop 2012, Chiang 2012, Senter 2014, Susswein 2015, Byers 2016, de Jonge 2018, Rebbeck 2018, Delgado-Balderas 2018, Gallardo-Rincon 2020). Based on the population data and the number of reported patients, the prevalence of the variant in affected individuals is significantly increased (ACMG PS4). In addition, multifactorial probability models, performing systematic assessments of BRCA variants, which included analysis of personal and family history of cancer, tumor pathology, co-occurrence in trans with known deleterious mutations and co-segregation with disease in pedigrees, predicted this variant to be likely deleterious (Easton 2007); and when the spliceogenic effect of the variant was also taken into account, this variant was predicted to be clearly pathogenic (posterior probability of pathogenicity: 0.999; Vallee 2016). These data indicate that the variant is very likely to be associated with disease. An in vitro study, examining the protein level effects of this missense change, demonstrated that the missense variant had comparable activity to the wild type in a transcriptional activation assay (Woods 2016); however, since authors used the BRCA1 cDNA sequence cloned into their vectors for mutagenesis, these data only represent the protein level effects of the missense change. Therefore, in light of the strong spliceogenic effect, this finding does not reflect the overall consequence of the variant. Ten 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 pathogenic (n=4) / likely pathogenic (n=6). Therefore, the community consensus seems to be converging on a pathological outcome for this variant. This variant was previously classified conservatively as a VUS-possibly pathogenic awaiting additional co-segregation in large families and functional evidence of the altered splice variant at the protein level. Based on the evidence outlined above, and further supported by ACMG guidelines (ACMG PM2, PS3 and PS4), the variant was classified as pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000048680 SCV000966914 likely pathogenic Hereditary breast and ovarian cancer syndrome 2017-07-20 criteria provided, single submitter clinical testing The p.Ala1623Gly variant in BRCA1 has been reported in >10 individuals with BRCA 1-associated cancers (Adem 2003, Easton 2007, Evans 2008, Walker 2010, Alsop 201 2, Chiang 2012, Breast Cancer Information Core (BIC) database). This variant has been identified in 1/11578 Latino chromosomes by the Exome Aggregation Consorti um (ExAC, http://exac.broadinstitute.org; dbSNP rs80356862) and has been reporte d in ClinVar (Variation ID: 37614). Computational prediction tools and conservat ion analysis suggest that this variant may not impact the protein; however, RNA analysis from affected individuals show that the p.Ala1623Gly variant causes a d eletion of 119 nucleotides in a fraction of transcripts Walker 2010). In summary , although additional studies are required to fully establish its clinical signi ficance, the p.Ala1623Gly variant is likely pathogenic. ACMG/AMP Criteria applie d: PS4, PM2, PS3_Supporting.
Research and Development, ARUP Laboratories RCV001659865 SCV001878392 pathogenic 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) RCV000031195 SCV000053795 pathogenic Breast-ovarian cancer, familial 1 2012-02-24 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031195 SCV000145198 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000496627 SCV000587430 uncertain significance not specified 2014-01-31 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353579 SCV000591543 likely pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The variant was identified in dbSNP (ID: rs80356862) “With Pathogenic allele”; Exome Aggregation Consortium database (August 8, 2016) in 1 of 121410 chromosomes (freq. 0.000008237) in the following populations: Latino in 1 of 11578 chromosomes (freq. 0.00008637), but was not seen in African, East Asian, European (Finnish), European (Non-Finnish), South Asian and Other populations, 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; ClinVar and Clinvitae database with conflicting interpretations of pathogenicity (likely pathogenic by GeneDx and Counsyl; uncertain significance by Invitae and BIC; pathogenic by Ambry Genetics); Fanconi Anemia Mutation Database (LOVD) 2X; BRCA Share UMD Mutations Database (6X as causal); BIC database (9X with unknown clinical importance); The p.Ala1623 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict the creation of a 5’ splice site. However, this information is not predictive enough to assume pathogenicity. In studies using three independent measures in the assessment of previously classified VUS variants: co-occurrence in trans of a VUS with known deleterious mutations; detailed analysis, by logistic regression, of personal and family history of cancer in VUS-carrying probands; and, in a subset of probands, an analysis of co-segregation with disease in pedigrees, the variant was determined with Odds of greater than 20:1 in Favor of Causality (Easton 2007). RT-PCR analysis identified a major splicing aberration for c.4868C>G (p.Ala1623Gly), resulting in an 119bp deletion from exon 16, and creating an aberrant splice product encoding a truncated protein. This resulted in elevated levels of an alternative mRNA isoform. Both wild-type and variant allele for BRCA1 c.4868C>G (p.Ala1623Gly) was present in subject samples from the UK and Australia (Walker 2010).rnIn summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.

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