Variant rs80359483 details in Genebe, Genetics Data Aggregator

Genes affected

BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]

BRCA2 links:

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 3880 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 13-32316508-GAC-G is Pathogenic according to our data. Variant chr13-32316508-GAC-G is described in ClinVar as [Pathogenic]. Clinvar id is 51814.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32316508-GAC-G is described in Lovd as [Pathogenic]. Variant chr13-32316508-GAC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.51_52del	p.Arg18LeufsTer12	frameshift_variant	2/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8 linkuse as main transcript	c.51_52del	p.Arg18LeufsTer12	frameshift_variant	2/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes

AF:

0.00000658

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152032

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0.00

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0.00

Gnomad NFE

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0.0000147

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0.00

GnomAD4 exome

AF:

6.84e-7

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1461656

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0.00

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727132

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Gnomad4 AFR exome

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0.00

Gnomad4 NFE exome

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8.99e-7

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0.00

GnomAD4 genome

AF:

0.00000658

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152032

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0.00

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74262

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0.00

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0.00

Gnomad4 NFE

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0.0000147

Gnomad4 OTH

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0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary breast ovarian cancer syndrome

Pathogenic:4

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	Labcorp Genetics (formerly Invitae), Labcorp	May 19, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 51814). This variant is also known as 277delAC and 279delAC. This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 8589730, 20104584, 26534844, 28324225). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg18Leufs*12) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 01, 2024	The p.Arg18LeufsX12 variant in BRCA2 has been reported in >10 individuals with BRCA2-associated cancers, including 2 males with breast cancer. This variant segregated with disease in one large family (exact numbers not disclosed; Tavtigian 1996 PMID: 8589730, Easton 1997 PMID: 9245992, Csokay 1999 PMID: 10070953, Seymour 2008 PMID: 18092194, Borg 2010 PMID: 20104584, Ding 2011 PMID: 20927582, Finkelman 2012 PMID: 22430266, Li 2016 PMID: 26534844, Meisel 2017 PMID: 28324225, Toss 2019 PMID: 30736435, Shao 2020 PMID: 31742824, Solano 2021 PMID: 34072659). This variant has also been identified in 0.0005% (2/418050) of European chromosomes in gnomAD (http://gnomad.broadinstitute.org, v4.0.0). In vitro functional studies support an impact on protein function as this variant did not rescue embryonic stem cell lethality in an in vitro functional assay (Kuznetsov 2008 PMID: 18607349). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 18 and leads to a premature termination codon 12 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer (HBOC). Additionally, this variant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID 51814). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PS4_Moderate, PM2_Supporting, PS3_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 30, 2021	Variant summary: BRCA2 c.51_52delAC (p.Arg18LeufsX12) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251254 control chromosomes. c.51_52delAC has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). 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. Multiple clinical diagnostic laboratories, an expert panel (ENIGMA) and a consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Breast-ovarian cancer, familial, susceptibility to, 2

Pathogenic:3

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	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 19, 2024	The c.51_52delAC pathogenic mutation, located in coding exon 1 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 51 and 52, causing a translational frameshift with a predicted alternate stop codon (p.R18Lfs*12). This pathogenic mutation has been observed in multiple individuals with breast, ovarian, and male breast cancer (Tavtigian SV et al. Nat. Genet.1996 Mar;12(3):333-7; Csokay B et al. Cancer Res.1999 Mar; 59(5):995-8; Borg A et al. Hum. Mutat. 2010 Mar;31(3):E1200-40; Ding YC et al. Breast Cancer Res. Treat. 2011 Apr; 126(3):771-8; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295(5):1227-1238; Rebbeck TR et al. Hum. Mutat. 2018 05;39(5):593-620). Of note, this alteration is also designated as 277delAC and 279delAC 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	Jun 08, 2021	This variant deletes 2 nucleotides in exon 2 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A functional study has reported that this variant impacts BRCA2 function in complementing Brca2-deficient mouse embryonic stem cells (PMID: 18607349). This variant has been reported in at least five individuals affected with breast cancer and ovarian cancer (PMID: 8589730, 10070953, 20104584, 34072659) and in suspected hereditary breast and ovarian cancer families (PMID: 22430266, 26534844, 28324225). This variant has been reported to segregate with male and female breast cancer and ovarian cancer in a large pedigree with a LOD score of 5.06 (PMID: 8589730, 9245992). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 21, 2016

This deletion of 2 nucleotides in BRCA2 is denoted c.51_52delAC at the cDNA level and p.Arg18LeufsX12 (R18LfsX12) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AGAC[AC]GCTG. The deletion causes a frameshift, which changes an Arginine to a Leucine at codon 18, and creates a premature stop codon at position 12 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA2 c.51_52delAC, previously reported as 277delAC and 279delAC, did not rescue the embryonic stem cell lethality in an in vitro functional assay, and was also observed to segregate with disease in at least one large hereditary breast/ovarian cancer family, consistent with its role as a pathogenic variant (Kuznetsov 2008, Tavtigian 1996). we consider this variant to be pathogenic. -

Malignant tumor of breast

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The p.Arg18LeufsX12 variant was identified in 2 of 1974 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer (Finkelman 2012, Tavtigian 1996). The variant was also identified in dbSNP (ID: rs80359483) â€šÃ„ÃºWith pathogenic alleleâ€šÃ„Ã¹, HGMD, LOVD, the ClinVar database (classified as a pathogenic variant by BIC and Ambry Genetics), and the BIC database (5X with clinical importance). A functional assay by Kuznetsov (2008) found that this mutation could not rescue mouse embryonic stem cell lethality, supporting its deleterious phenotype. The p.Arg18LeufsX12 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 18 and leads to a premature stop codon 12 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 BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. -

Familial cancer of breast

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneKor MSA

Jul 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

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SpliceAI score (max)

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Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

rs80359483

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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