ClinVar Genomic variation as it relates to human health

IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.9999

The variant disrupts a canonical splice site, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity.

The BRCA1 c.4357+1G>A variant (rs80358027), also known as IVS13+1G>A, is reported in the literature in multiple individuals affected with breast and/or ovarian cancer (Alemar 2016, Carter 2018, Pal 2004, Thomassen 2012). This variant is found on a single chromosome in the Genome Aggregation Database (1/251154 alleles), indicating it is not a common polymorphism. This variant abolishes the canonical splice acceptor site of intron 13, which is likely to disrupt gene function. Consistent with this, RNA analyses from a patient carrying this variant demonstrate skipping of exon 13, leading to a frameshift (Thomassen 2012). Based on available information, this variant is considered to be pathogenic. References: Alemar B et al. Prevalence of Hispanic BRCA1 and BRCA2 mutations among hereditary breast and ovarian cancer patients from Brazil reveals differences among Latin American populations. Cancer Genet. 2016 Sep;209(9):417-422. PMID: 27425403. Carter NJ et al. Germline pathogenic variants identified in women with ovarian tumors. Gynecol Oncol. 2018 Dec;151(3):481-488. PMID: 30322717. Pal T et al. BRCA1 and BRCA2 mutations in a study of African American breast cancer patients. Cancer Epidemiol Biomarkers Prev. 2004 Nov;13(11 Pt 1):1794-9. PMID: 15533909. Thomassen M et al. Characterization of BRCA1 and BRCA2 splicing variants: a collaborative report by ENIGMA consortium members. Breast Cancer Res Treat. 2012 Apr;132(3):1009-23. PMID: 21769658.

Canonical splice site variant demonstrated to result skipping of exon 12 which is predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease (Thomassen 2012, Steffensen 2014); Observed in individuals with BRCA1-related cancers (Pal 2004, Thomassen 2012, Couch 2015, Pal 2015, Alemar 2016, Frey 2017, Delgado-Balderas 2018, Isaacsson Velho 2018); Multifactorial studies suggest this variant is associated with breast and ovarian cancer (Easton 2007, Lindor 2012); Classified as pathogenic by a well-established clinical consortium and/or database (ClinVar); Also known as 4476+1G>A (IVS13+1G>A); This variant is associated with the following publications: (PMID: 17924331, 30787465, 21735045, 15533909, 26287763, 24013928, 24797986, 20838878, 19241424, 25920394, 27425403, 25085752, 25525159, 28495237, 28476184, 25452441, 20104584, 26295337, 29368341, 28918466, 29997359, 26681312, 29907814, 30702160, 29446198, 30720243, 30322717, 21769658, 24667779, 33646313, 31447099, 31825140, 21990134)

Variant summary: The BRCA1 c.4357+1G>A variant involves the alteration of a conserved intronic nucleotide located at the canonical splicing site. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict that this variant abolishes the 5' splicing donor site. These predictions have been confirmed by RT-PCR showing that it leads to skipping of exon 12 (legacy exon 13) and frameshift p.Arg1397TyrfsX2 (Thomassen_2011). This variant was found in 1/121252 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). It has also been reported in multiple HBOC patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

This c. 4357+1G>A (also known as IVS13+1G>A) variant in the BRCA1 gene has been reported in multiple patients with breast cancer from two families breast cancer patients (PMID15533909, PMID21769658). In the first family, The first patientthe proband was diagnosed at 30 years of age and with three female relatives of the proband were diagnosed with breast cancer before age 40 (PMID 5533909). The second patient in the second family was diagnosed at 26 years of age without with no known family history (PMID21769658). In silico analysis and experimental studies suggest that this variant causes exon 13 skipping (PMID24667779,21735045, 21769658). A multifactorial likelihood algorithm also predicts this variant to be deleterious (PMID 17924331). Based on the current evidence, this c. 4357+1G>A variant in the BRCA1 gene is classified as pathogenic.

The BRCA1 c.4357+1G>A variant results in a substitution at the consensus splice donor site. A functional study conducted in patient cells demonstrated that this variant results in abnormal splicing which is predicted to result in a frameshift and premature termination of translation, leading to nonsense mediated mRNA decay (PMID: 21769658). Across a selection of the available literature, this variant has been identified in more than ten individuals with breast or ovarian cancer, including 5% of African American patients in a multi-center cohort (PMID: 21769658; PMID: 27425403; PMID: 29446198; PMID: 30322717; PMID: 31825140). This variant has also been detected in an individual with prostate cancer (PMID: 29368341). This variant is reported in the Genome Aggregation Database in one allele at a frequency of 0.000046 in the European (Finnish) population This variant has been classified as pathogenic by at least three submitters in ClinVar. Based on the available evidence, the c.4357+1G>A variant has been classified as pathogenic for hereditary breast and ovarian cancer.

This variant causes a G to A nucleotide substitution at the +1 position of intron 12 of the BRCA1 gene. RNA studies have reported this variant to cause the out-of-frame skipping of exon 12 in carrier RNA and in minigene splicing assay (PMID: 21769658, 24667779 ), resulting in an unstable mRNA transcript (PMID: 21769658). This variant has been observed in multiple individuals and families affected with breast and ovarian cancer (PMID: 15533909, 20104584, 21769658, 23458327, 24797986, 25452441, 27425403, 30322717) and prostate cancer (PMID: 29368341). This variant has been identified in 1/251154 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

This sequence change affects a donor splice site in intron 12 of the BRCA1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs80358027, gnomAD 0.004%). Disruption of this splice site has been observed in individual(s) with breast cancer (PMID: 15533909, 20104584, 24013928, 24797986, 25085752, 25452441, 26681312). This variant is also known as IVS13+1G>A. ClinVar contains an entry for this variant (Variation ID: 37584). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 17924331). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 21735045, 21769658, 24667779; Invitae). For these reasons, this variant has been classified as Pathogenic.

The c.4357+1G>A variant (also known IVS13+1G>A) in BRCA1 has been reported in >30 individuals with breast, ovarian or other associated cancers and segregated with disease in 3 affected individuals from 1 family (Pal 2004 PMID: 15533909, Couch 2015 PMID:25452441, Susswein 2016 PMID: 26681312, Tihomirova 2014 PMID: 24797986, Thomassen 2012 PMID: 21769658, Isaacsson 2018 PMID: 29368341, Alemar 2016 PMID: 27425403, Carter 2018 PMID: 30322717, Akbari 2014 PMID:23458327). It has also been identified in 0.005% (1/21620) of Finnish chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant was classified as Pathogenic on August 10, 2015 by the ClinGen-approved Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) expert panel (Variation ID 37584). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the BRCA1 gene is an established disease mechanism in autosomal autosomal dominant HBOC. Multifactorial likelihood algorithm using genetic, in silico, and statistical data determined to have a high probability of being pathogenic (Easton 2007 PMID: 17924331, Lindor 2012 PMID: 21990134, Pruss 2014 PMID: 25085752). Experimental studies have shown that this variant causes exon 12 skipping in BRCA1 (Steffensen 2014 PMID: 24667779, Thomassen 2012 PMID: 21769658). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PS4, PVS1_Strong, PM2, PM5, PS3_Supporting.

The c.4357+1G>A intronic variant results from a G to A substitution one nucleotide after exon 12 (coding exon 11) of the BRCA1 gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). This mutation has been reported in multiple individuals with personal and/or family history consistent with hereditary breast and ovarian cancer (HBOC) syndrome (Pal, 2004; Akbari, 2014; Tihomirova, 2014; Couch, 2015; Alemar, 2016; Rebbeck, 2018). Functional analyses have demonstrated that this alteration leads to a skipping of coding exon 11 (also known as exon 13), causing a frameshift and alternate stop codon (Ambry internal data; Thomassen, 2012). In addition, this alteration has been classified as pathogenic (p>0.99) by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence (Easton, 2007; Lindor, 2012; Vallee, 2012). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic.