ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4484G>T (p.Arg1495Met) (rs80357389)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131886 SCV000186941 pathogenic Hereditary cancer-predisposing syndrome 2017-08-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Functionally-validated splicing mutation,Last nucleotide of exon,Other strong data supporting pathogenic classification
Baylor Genetics RCV000462940 SCV000540946 pathogenic Familial cancer of breast 2017-02-23 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031179 SCV000145100 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770739 SCV000902222 pathogenic Breast and/or ovarian cancer 2016-05-17 criteria provided, single submitter clinical testing
Color RCV000131886 SCV000537652 pathogenic Hereditary cancer-predisposing syndrome 2015-10-05 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031179 SCV000325979 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000048576 SCV000591519 pathogenic Hereditary breast and ovarian cancer syndrome 2015-04-17 criteria provided, single submitter clinical testing
GeneDx RCV000159992 SCV000210177 pathogenic not provided 2018-11-20 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.4484G>T at the cDNA level. Located at the last nucleotide of exon 13, it disrupts the natural splice donor site and causes abnormal splicing. Multiple protein and RNA analyses have consistently demonstrated that BRCA1 c.4484G>T causes skipping of exon 13, and to a lesser extent, skipping of exons 13-14 (also referred to as exons 14 and 15 in the literature) and subsequently fails to produce a full length transcript (Ozcelik 1999, Yang 2003, Houdayer 2012, Colombo 2013, Santos 2014). BRCA1 c.4484G>T, also known as 4603G>T using alternate nomenclature, has been reported in multiple individuals with personal and/or family histories of breast and ovarian cancer, segregating with cancer in at least one of these families (Aziz 2001, Caux-Moncoutier 2011, Zhang 2011, Lara 2012, Ripamonti 2013, Santos 2014, Pal 2015, Finch 2015, Pellegrino 2016, Brianese 2017). Additionally, this variant was strongly predicted by Lindor et al. (2012) to be deleterious based on tumor pathology, clinical histories, family studies and co-occurrence with deleterious variants. Although the nucleotide substitution results in the change of an Arginine to a Methionine at codon 1495, and is called Arg1495Met in the literature, we are using the nucleotide nomenclature to refer to the variant since the defect is determined to be one of splicing rather than a resulting missense variant. BRCA1 c.4484G>T was not observed at a significant allele frequency in large population cohorts (Lek 2016). The nucleotide which is altered, a guanine (G) at base 4484, is conserved across species. Based on the current evidence, we consider BRCA1 c.4484G>T to be a pathogenic variant.
GeneKor MSA RCV000238601 SCV000296803 pathogenic not specified 2016-07-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000048576 SCV000699152 pathogenic Hereditary breast and ovarian cancer syndrome 2016-07-31 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.4484G>T (p.Arg1495Met) variant causes a missense change involving a conserved nucleotide, located at the most 3' position, i.e., the last nucleotide of exon 13. It is predicted to disrupt the natural splice donor site and cause abnormal splicing. 5/5 splicing prediction tools, predict alterations to splicing, consistent with the observed functional studies that implicate an affect on splicing. The variant of interest was observed in a large, broad control population, ExAC, with an allele frequency of 1/121358, which does not exceed the estimated maximal expected allele frequency for a pathogenic BRCA1 variant of 1/1000. The variant of interest has been reported in multiple affected individuals via publications, along with multiple reputable databases/clinical laboratories citing the variant as "pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Pathogenic.
Invitae RCV000048576 SCV000076589 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with methionine at codon 1495 of the BRCA1 protein (p.Arg1495Met). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and methionine. This variant also falls at the last nucleotide of exon 13 of the BRCA1 coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs80357389, ExAC 0.001%). This variant has been reported in individuals affected with breast and ovarian cancer (PMID: 23096355, 10571952, 10923033, 22144684). It has also been shown to co-segregate with disease in a family affected with breast cancer (PMID: 24607278). This variant is also known as 4603G>T in the literature. ClinVar contains an entry for this variant (Variation ID: 37598) Experimental studies evaluating the effect of this sequence change on RNA splicing have shown that this variant results in aberrant BRCA1 splicing, leading to the skipping of exon 13 as well as exons 13-14 (PMID: 24607278, 10571952, 12915465, 21120943). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000048576 SCV000605750 pathogenic Hereditary breast and ovarian cancer syndrome 2017-02-25 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Mendelics RCV000048576 SCV000839231 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Pathway Genomics RCV000031179 SCV000223754 pathogenic Breast-ovarian cancer, familial 1 2014-10-30 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000159992 SCV000296380 pathogenic not provided 2015-09-04 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000048576 SCV000587401 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000031179 SCV000053779 pathogenic Breast-ovarian cancer, familial 1 2012-05-01 no assertion criteria provided clinical testing

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