rs397507683

chr13-32338103-G-GA

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.3751dup(p.Thr1251AsnfsTer14) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,568 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: 6.9e-7 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:18
• Conservation: PhyloP100: 1.17

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 13-32338103-G-GA is Pathogenic according to our data. Variant chr13-32338103-G-GA is described in ClinVar as [Pathogenic]. Clinvar id is 51516.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.3751dup	p.Thr1251AsnfsTer14	frameshift_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.3751dup	p.Thr1251AsnfsTer14	frameshift_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000407 AC: 1 AN: 245816 Hom.: 0 AF XY: 0.00000753 AC XY: 1 AN XY: 132730

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: 0.00

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457568 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 724600

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Mar 14, 2022	- -
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	Department of Medical Genetics, Oslo University Hospital	Jul 01, 2015	- -
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, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 03, 2017	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 22, 2022	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; 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 3979dupA and 3976insA; This variant is associated with the following publications: (PMID: 12100744, 34637943, 29922827, 33754277, 12112655, 17826769, 25418591, 26187060, 12442265, 27165220, 29339979, 30720243, 30014164, 30489631, 21156238, 29446198, 32658311, 34426522, 31851867, 35418818, 33629534, 35216584, Gezdirici_2021) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 23, 2022	The c.3751dupA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a duplication of A at nucleotide position 3751, causing a translational frameshift with a predicted alternate stop codon (p.T1251Nfs*14). This alteration was identified in a Turkish patient with ovarian cancer as well as an Iranian patient with early onset breast cancer (Yazici H et al. Hum. Mutat., 2002 Jul;20:28-34; Kwong A et al. J. Med. Genet., 2016 Jan;53:15-23). Of note, this alteration is also designated as 3976insA and 3979insA 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	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Aug 15, 2018	This frameshifting variant in exon 11 of 28 introduces a premature stop codon and is predicted to result in loss of normal protein function. This variant has been previously reported as a disease-causing variant in the literature (PMID: 29339979 , 26187060, 12112655, 27165220). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0004% (1/240830) and thus is presumed to be rare. Based on the available evidence, the c.3751dupA (p.Thr1251AsnfsTer14) is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 16, 2021	This variant inserts 1 nucleotide in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 3976insA or 3979insA in the nomenclature. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least two individuals affected with breast or ovarian cancer (PMID: 12100744, 12112655, 33471991; Leiden Open Variation Database DB-ID BRCA2_001195) and a suspected hereditary breast and ovarian cancer family (PMID: 29339979). This variant has been identified in 1/245816 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. -

Hereditary breast ovarian cancer syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 19, 2022	Variant summary: BRCA2 c.3751dupA (p.Thr1251AsnfsX14) 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 4.1e-06 in 245816 control chromosomes (gnomAD). The variant, c.3751dupA, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (examples: Heramb_2018, Yassaee_2002, Yazici_2002). 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. Twelve ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 03, 2022	The p.Thr1251AsnfsX14 variant in BRCA2 has been reported in at least 3 individuals affected with breast cancer and segregated with disease in 1 affected family member (Yassaee 2002 PMID: 12100744, Yazici 2002 PMID: 12112655, Kwong 2015 PMID: 26187060, Heramb 2018 PMID: 29339979). This variant was classified as Pathogenic on September 8, 2016 by the ClinGen-approved Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (Variation ID 51516) and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1251 and leads to a premature termination codon 14 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer (HBOC) syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PM2_Supporting, PVS1, PS4_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 27, 2023	This sequence change creates a premature translational stop signal (p.Thr1251Asnfs*14) 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 (rs397507683, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast cancer and ovarian cancer (PMID: 12112655, 17826769, 27165220). This variant is also known as c.3976insA and c.3979insA. ClinVar contains an entry for this variant (Variation ID: 51516). For these reasons, this variant has been classified as Pathogenic. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 31, 2023

- -

Breast carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences

Aug 18, 2021

Invasive Ductal Carcinoma Estrogen Receptor: Positive Progesterone Receptor: Positive HER2 Receptor: Positive -

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: rs397507683; hg19: chr13-32912240;