rs80357872
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.514del(p.Gln172AsnfsTer62) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,276 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. Q172Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_007294.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA1 | NM_007294.4 | c.514del | p.Gln172AsnfsTer62 | frameshift_variant | 7/23 | ENST00000357654.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA1 | ENST00000357654.9 | c.514del | p.Gln172AsnfsTer62 | frameshift_variant | 7/23 | 1 | NM_007294.4 | P4 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152214Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251472Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135908
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461062Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 726930
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152214Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74358
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Apr 26, 2021 | The BRCA1 c.514delC variant is classified as Pathogenic (PVS1, PM2_Supporting, PP5) This BRCA1 c.514delC variant is located in exon Missing Exon and is predicted to cause a shift in the reading frame at codon 172. This variant is absent from population databases (PM2). The variant has been reported in dbSNP (rs80357872) and has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 55421). It has not been reported in HGMD. literature: Finch et al., 2016, PMID:26219728, Wong-Brown et al., 2015, PMID:25682074, Ghiorzo et al., 2012, PMID:21989927, Miolo et al., 2009, PMID:19818148, Tai et al., 2007, PMID:18042939, Russo et al., 2007, PMID:17221156, Nanda et al., 2005, PMID:16234499, van Orsouw et al., 1999, PMID:10528853, Azzollini et al., 2016, PMID:27062684, Nedelcu et al., 2002, PMID:11938448, Lu et al., 2015, PMID:26689913, Huang et al., 2018, PMID:29625052, Fanale et al., 2020, PMID:32854451 - |
Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The p.Gln172AsnfsX62 deletion variant has been previously reported in the literature in at least 2 of 178 proband chromosomes in individuals or families with pancreatic and breast cancer (Ghiorzo 2012, van Orsouw 1999). The variant was also reported in HGMD, the UMD (3x as causal) and in the BIC (23x as clinically important) databases. It is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 172 and leads to a premature stop codon 62 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of hereditary breast and ovarian cancer. In summary, based on the above information, this variant is classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | Dec 30, 1999 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 29, 2024 | - - |
Pathogenic, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Apr 22, 2016 | Variant allele predicted to encode a truncated non-functional protein. - |
Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Nov 23, 2009 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge | Oct 02, 2015 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 25, 2023 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in several Hereditary Breast and Ovarian Cancer families (van Orsouw et al., 1999; Tai et al., 2007; Ghiorzo et al., 2012; Finch et al., 2015; Incorvaia et al., 2020); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 633delC; This variant is associated with the following publications: (PMID: 27157322, 26219728, 25682074, 17591842, 20682393, 32438681, 28888541, 10528853, 18042939, 17221156, 27376475, 27566247, 21989927, 30128899, 29922827, 29907814, 29337092, 29625052, 26689913, 32854451, 30787465, 36139606, 34178674, 33573335, 32380732) - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 03, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 25, 2022 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:3
Pathogenic, no assertion criteria provided | research | Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto | Jan 31, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 21, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 55421). This variant is also known as 633delC. This premature translational stop signal has been observed in individual(s) with breast, ovarian and pancreatic cancer (PMID: 10528853, 17591842, 21989927, 25682074, 26219728). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln172Asnfs*62) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 10, 2024 | Variant summary: BRCA1 c.514delC (p.Gln172AsnfsX62) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4e-06 in 251472 control chromosomes. c.514delC has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27062684, 18042939, 25682074). ClinVar contains an entry for this variant (Variation ID: 55421). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 15, 2021 | The c.514delC pathogenic mutation, located in coding exon 6 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 514, causing a translational frameshift with a predicted alternate stop codon (p.Q172Nfs*62). This mutation has been reported in multiple individuals and families affected with hereditary breast and ovarian cancer (HBOC) syndrome (van Orsouw NJ et al. J Med Genet. 1999 Oct;36(10):747-53; Nedelcu R et al. Eur. J. Hum. Genet. 2002 Feb;10(2):150-2; Nanda R et al. JAMA 2005 Oct;294(15):1925-33; Russo A et al. Breast Cancer Res. Treat. 2007 Nov;105(3):267-76; Tai YC et al. J Natl Cancer Inst. 2007 Dec;99(23):1811-4; Miolo G et al. BMC Cancer 2009 Oct;9:360; Ghiorzo P et al. Fam Cancer. 2012 Mar;11(1):41-7; Incorvaia L et al. Cancers (Basel), 2020 May;12; Fanale D et al. Cancers (Basel), 2020 Aug;12). Of note, this alteration is also designated as 633delC in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 28, 2023 | This variant deletes 1 nucleotide in exon 7 of the BRCA1 gene, creating a frameshift and premature translation stop signal. It is also known as 633delC according to the BIC nomenclature. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in individuals with breast and/or ovarian cancer (PMID: 10528853, 17221156, 17591842, 25682074, 26219728) and pancreatic cancer (PMID: 21989927). This variant has been identified in 1/251472 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. - |
Breast and/or ovarian cancer Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research | Dec 03, 2013 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at