ClinVar Miner

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

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Total submissions: 14
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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 2019-11-20 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 2018-05-09 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4868C>G at the cDNA level, p.Ala1623Gly (A1623G) at the protein level, and results in the change of an Alanine to a Glycine (GCT>GGT). This variant, also reported as 4987C>G by alternative nomenclature, has been observed in individuals with breast and ovarian cancer (Adem 2003, Evans 2008, Alsop 2012, Chiang 2012). BRCA1 Ala1623Gly has also been reported in a family where it segregated in individuals with breast, ovarian, and pancreatic cancer (Senter 2014). In vitro studies have demonstrated that this variant results in abnormal gene splicing causing a deletion of 119 nucleotides of the BRCA1 gene, resulting in disruption to the open reading frame; however, one author has noted this abnormal splicing to be incomplete (Walker 2010, Byers 2016). Easton et al. (2007) report 31:1 odds in favor of causality based on personal and family history of cancer, co-occurrence, and co-segregation data. BRCA1 Ala1623Gly was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in a region known to interact with multiple proteins (Paul 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider BRCA1 Ala1623Gly to be a likely pathogenic variant.
Ambry Genetics RCV000131686 SCV000186722 pathogenic Hereditary cancer-predisposing syndrome 2018-04-25 criteria provided, single submitter clinical testing In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Functionally-validated splicing mutation;Other strong data supporting pathogenic classification
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
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000048680 SCV000591543 likely pathogenic Hereditary breast and ovarian cancer syndrome 2016-08-31 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 RCV000131686 SCV000683223 likely pathogenic Hereditary cancer-predisposing syndrome 2019-12-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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,; 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.
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

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