rs397507375

Positions:

• chr13-32341077-CAG-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000059.4(BRCA2):​c.6724_6725del​(p.Asp2242PhefsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,646 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. T2241T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:14
• Conservation: PhyloP100: 3.43

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-32341077-CAG-C is Pathogenic according to our data. Variant chr13-32341077-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 38062.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32341077-CAG-C is described in Lovd as [Pathogenic]. Variant chr13-32341077-CAG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.6724_6725del	p.Asp2242PhefsTer2	frameshift_variant	11/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.6724_6725del	p.Asp2242PhefsTer2	frameshift_variant	11/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251336 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135848

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461646 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 727142

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:4

Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Sep 08, 2016	Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 09, 2023	This variant deletes 2 nucleotides in exon 11 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. This variant has been reported in individuals affected with breast and/or ovarian cancer and in high-risk breast and ovarian cancer families (PMID: 19656164, 22217648, 22382806, 22798144, 25863477, 26187060, 27836010, doi:10.21203/rs.3.rs-734551/v1), and has also been identified in 6 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). This variant has been identified in 1/251336 chromosomes 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Feb 14, 2011	- -

Hereditary breast ovarian cancer syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 14, 2023	This sequence change creates a premature translational stop signal (p.Asp2242Phefs*2) 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). This variant is present in population databases (rs397507375, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 19656164, 22217648, 22382806, 22798144, 25863477). This variant is also known as 6952delGA. ClinVar contains an entry for this variant (Variation ID: 38062). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jul 05, 2018	The c.6724_6725del (p.Asp2242Phefs*2) variant in the BRCA2 gene is located on the exon 11 and is predicted to shift the reading frame that introduces a premature translation termination codon (p.Asp2242Phefs*2), resulting in an absent or disrupted protein product. The variant has been reported in multiple individuals with breast and/or ovarian cancer (PMID: 34657357, 22217648, 19656164, 26187060). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 8988179, 11897832, 29446198). The variant is reported in ClinVar as pathogenic (ID: 38062) and reviewed by the expert panel. The variant is rare in general population according to gnomAD (1/251336). Therefore, the c.6724_6725del (p.Asp2242Phefs*2) variant in the BRCA2 gene has been classified as pathogenic. -
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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 11, 2023	Variant summary: BRCA2 c.6724_6725delGA (p.Asp2242PhefsX2) 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. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251336 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6724_6725delGA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g., Kang_2015). 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 publication was ascertained in the context of this evaluation (PMID: 25863477). Seven ClinVar submitters (evaluation after 2014) have cited the variant, and all submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 10, 2023	The BRCA2 c.6724_6725del; p.Asp2242PhefsTer2 variant (rs397507375), also known as 6952delGA, is reported in individuals with breast cancer (Bang 2022, Ryu 2019, Seong 2009). This variant is also reported in ClinVar (Variation ID: 38062). It is only found on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting two nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Bang YJ et al. Clinicopathological Characterization of Double Heterozygosity for BRCA1 and BRCA2 Variants in Korean Breast Cancer Patients. Cancer Res Treat. 2022 Jul;54(3):827-833. PMID: 34645131. Ryu JM et al. Prevalence and oncologic outcomes of BRCA 1/2 mutations in unselected triple-negative breast cancer patients in Korea. Breast Cancer Res Treat. 2019 Jan;173(2):385-395. PMID: 30350268. Seong MW et al. Comprehensive mutational analysis of BRCA1/BRCA2 for Korean breast cancer patients: evidence of a founder mutation. Clin Genet. 2009 Aug;76(2):152-60. PMID: 19656164. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 28, 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; Reported in association with hereditary breast and ovarian cancer, and identified as a recurrent pathogenic variant in individuals of Korean ancestry (Han et al., 2011; Kwong et al., 2016; Ryu et al., 2019); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at a significant frequency in large population cohorts (gnomAD); Also known as 6952_6953del; This variant is associated with the following publications: (PMID: 25863477, 29922827, 19656164, 27836010, 26187060, 29446198, 22798144, 29346284, 30350268, 21497495, 30720243, 31447099, 34645131) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 29, 2018	This variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. Additionally, this variant has been reported in an individual with breast cancer in the published literature (PMID: 19656164 (2009)). Based on the available information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 16, 2022	This variant deletes 2 nucleotides in exon 11 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. This variant has been reported in individuals affected with breast and/or ovarian cancer and in high-risk breast and ovarian cancer families (PMID: 19656164, 22217648, 22382806, 22798144, 25863477, 26187060, 27836010, doi:10.21203/rs.3.rs-734551/v1), and has also been identified in 6 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). This variant has been identified in 1/251336 chromosomes 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 13, 2021	The c.6724_6725delGA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 6724 to 6725, causing a translational frameshift with a predicted alternate stop codon (p.D2242Ffs*2). This mutation has been reported in multiple Korean patients and families with breast and/or ovarian cancer, including individuals diagnosed with triple negative breast cancer (Kwong A et al. J Med Genet. 2016 Jan;53:15-23; Rebbeck TR et al. Hum. Mutat. 2018 May;39:593-620; Ryu JM et al. Breast Cancer Res Treat. 2019 Jan;173:385-395). 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. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs397507375; hg19: chr13-32915214;