rs80359271

Positions:

• chr13-32332715-CT-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.1238delT​(p.Leu413fs) 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 1,461,218 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). 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:16
• Conservation: PhyloP100: -0.0900

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 (HGNC:):

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 13-32332715-CT-C is Pathogenic according to our data. Variant chr13-32332715-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 37731.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32332715-CT-C is described in Lovd as [Pathogenic]. Variant chr13-32332715-CT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.1238delT	p.Leu413fs	frameshift_variant	10/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.1238delT	p.Leu413fs	frameshift_variant	10/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.869delT	p.Leu290fs	frameshift_variant	10/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.1238delT		non_coding_transcript_exon_variant	9/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 249956 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135372

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461218 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 726870

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: reviewed by expert panel

Submissions by phenotype

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

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	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
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)	Jan 06, 2014	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 17, 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; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 1466del; This variant is associated with the following publications: (PMID: 21120943, 25007954, 31794323, 31336956, 32719484, 32438681, 16847550, 16760289, 24065114, 26306726, 32058061, 32854451, 34178674, 21702907, 32380732, 29907814, 26317927, 25395318, 20104584, 36292577, 34917121, 32365798) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 24, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 28, 2023	This variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. In the published literature, this variant has been reported in individuals with a personal or family history of breast and/or ovarian cancer (PMIDs: 16847550 (2006), 16760289 (2006), 21120943 (2011), 26317927 (2016), 29907814 (2018), 31336956 (2019), 32380732 (2020), 3284451 (2020), 32438681 (2020), 33471991 (2021), 36292577 (2022)), including cases of male breast cancer (PMIDs: 16847550 (2006), 32058061 (2020), 32365798 (2020)). This variant has been noted as a common variant found within the Italian population (PMIDs: 16847550 (2006), 31336956 (2019), 32380732 (2020), 32854451 (2020), 32058061 (2020), 324386814 (2020), 32365798 (2020)). The frequency of this variant in the general population, 0.000004 (1/249956 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Hereditary breast ovarian cancer syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 14, 2023	Variant summary: BRCA2 c.1238delT (p.Leu413HisfsX17) 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 allele was found at a frequency of 4e-06 in 249956 control chromosomes (gnomAD). c.1238delT has been reported in the literature and in at least one clinical database in multiple individuals and families affected with breast and/or ovarian cancer (e.g. Giannini_2006, Caux-Moncoutier_2011, Manie_2016, Coppa_2014, Tedaldi_2020, BIC database). 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. Nine submitters, including an expert panel (ENIGMA), have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	This sequence change creates a premature translational stop signal (p.Leu413Hisfs*17) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with a personal and/or family history of breast cancer (PMID: 16760289, 21120943, 26306726). This variant is also known as 1466delT. ClinVar contains an entry for this variant (Variation ID: 37731). For these reasons, this variant 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	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 10, 2023	This variant deletes 1 nucleotide in exon 10 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 or ovarian cancer (PMID: 16760289, 16847550, 18092194, 21120943, 25395318, 26306726, 27062684, 27153395, 31336956). This variant has been identified in 1/249956 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	May 08, 2024	The c.1238delT pathogenic mutation, located in coding exon 9 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 1238, causing a translational frameshift with a predicted alternate stop codon (p.L413Hfs*17). This alteration has been identified in numerous Italian families with bilateral breast cancer, male breast cancer, and ovarian cancer histories (Capalbo C et al. Ann. Oncol., 2006 Jun;17 Suppl 7:vii34-40; Giannini G et al. Breast Cancer Res Treat, 2006 Nov;100:83-91; Minucci A et al. Expert Rev Mol Diagn, 2015 Aug;15:1383-403; Fanale D et al. Cancers (Basel), 2020 Aug;12(9); Incorvaia L et al. Cancers (Basel), 2020 May;12(5)). 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. -

Fanconi anemia complementation group D1 Pathogenic:1

Pathogenic, criteria provided, single submitter

not provided

Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin

-

- -

BRCA2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2019

The BRCA2 c.1238delT (p.Leu413HisfsTer17) variant results in a frameshift, and is predicted to result in premature termination of the protein. The p.Leu413HisfsTer17 has been reported in eight studies in which it has been identified in a heterozygous state in at least 11 individuals with hereditary cancer, either breast cancer, breast cancer and ovarian cancer or ovarian cancer alone (Capalbo et al. 2006; Giannini et al. 2006; Caux-Moncoutier et al. 2011; Concolino et al.2014; Coppa et al. 2014; Minucci 2015; Manie et al. 2016; Palmero et al. 2018). The variant is reported at a frequency of 0.000009 in the European (non-Finnish) population from the Genome Aggregation Database but this is based on one allele in a region of good sequencing coverage, so the variant is presumed to be rare. Although the c.3201+1G>C variant has not been reported in the literature in individuals with Fanconi anemia, it cannot be ruled out of causing this condition based on allele frequency in consideration of condition penetrance and prevalence estimates. Based on the evidence and the potential impact of frameshift variants, the BRCA2 p.Leu413HisfsTer17 variant is classified as pathogenic for hereditary breast and ovarian cancer. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 11, 2024

- -

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: rs80359271; hg19: chr13-32906852;