chr13-32333283-G-GA

Variant names:

• chr13-32333283-G-GA
• rs80359306
• NM_000059.4:c.1813dupA

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS3 PP5_Very_Strong

The NM_000059.4(BRCA2):​c.1813dupA​(p.Ile605AsnfsTer11) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,601,314 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000918819: Functional study showed variant with diminished DNA double strand break repair capacity (Becker_2012).; SCV000186437: This alteration, in compound heterozygosity with another BRCA2 mutation, was also reported in an individual with Fanconi anemia (Myers, 2012). The c.1813dupA pathogenic mutation was reported in two unrelated probands with a personal and/or family history of breast/ovarian cancers and was shown to diminish DNA double strand break repair capacity in response to irradiation (Becker , 2012).; SCV004562779: Functional data indicate that cell lines derived from patients harboring the c.1813dup variant are more susceptible than wild-type to radiation induced chromosomal abnormalities (Becker 2012). PMID:22729890.; SCV000805657: A functional in vitro study using blood lymphocytes on this variant has demonstrated significantly higher radiation-induced chromosomal aberrations (Becker et al. 2012. PubMed ID: 22729890).". Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:57 O:3
• Conservation: PhyloP100: 0.512
• Publications: 23 publications found

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 Gene-Disease associations (from GenCC):

• BRCA2-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• breast-ovarian cancer, familial, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Fanconi anemia complementation group D1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• pancreatic cancer, susceptibility to, 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• medulloblastoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000918819: Functional study showed variant with diminished DNA double strand break repair capacity (Becker_2012).; SCV000186437: This alteration, in compound heterozygosity with another BRCA2 mutation, was also reported in an individual with Fanconi anemia (Myers, 2012). The c.1813dupA pathogenic mutation was reported in two unrelated probands with a personal and/or family history of breast/ovarian cancers and was shown to diminish DNA double strand break repair capacity in response to irradiation (Becker , 2012).; SCV004562779: Functional data indicate that cell lines derived from patients harboring the c.1813dup variant are more susceptible than wild-type to radiation induced chromosomal abnormalities (Becker 2012). PMID: 22729890.; SCV000805657: A functional in vitro study using blood lymphocytes on this variant has demonstrated significantly higher radiation-induced chromosomal aberrations (Becker et al. 2012. PubMed ID: 22729890).
• PP5: Variant 13-32333283-G-GA is Pathogenic according to our data. Variant chr13-32333283-G-GA is described in ClinVar as Pathogenic. ClinVar VariationId is 37762.Status of the report is reviewed_by_expert_panel, 3 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000059.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	NM_000059.4	MANE Select	c.1813dupA	p.Ile605AsnfsTer11	frameshift	Exon 10 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.1813dupA	p.Ile605AsnfsTer11	frameshift	Exon 10 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.1813dupA	p.Ile605AsnfsTer11	frameshift	Exon 10 of 27	NP_001393649.1	A0A8V8TPZ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.1813dupA	p.Ile605AsnfsTer11	frameshift	Exon 10 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.1813dupA	p.Ile605AsnfsTer11	frameshift	Exon 10 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.1444dupA	p.Ile482AsnfsTer11	frameshift	Exon 10 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes AF: 0.0000264 AC: 4 AN: 151588 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000129 AC: 3 AN: 232106 AF XY: 0.00000793

Gnomad AFR exome AF: 0.0000656

Gnomad AMR exome AF: 0.0000325

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000942

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000124 AC: 18 AN: 1449726 Hom.: 0 Cov.: 35 AF XY: 0.0000139 AC XY: 10 AN XY: 720972

African (AFR) AF: 0.0000308 AC: 1 AN: 32496

American (AMR) AF: 0.0000239 AC: 1 AN: 41794

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25680

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39622

South Asian (SAS) AF: 0.00 AC: 0 AN: 83414

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53182

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 0.00000902 AC: 10 AN: 1108076

Other (OTH) AF: 0.0000669 AC: 4 AN: 59776

GnomAD4 genome AF: 0.0000264 AC: 4 AN: 151588 Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 73980

African (AFR) AF: 0.00 AC: 0 AN: 41304

American (AMR) AF: 0.00 AC: 0 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10434

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000589 AC: 4 AN: 67878

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
18	-	-	Breast-ovarian cancer, familial, susceptibility to, 2 (18)
16	-	-	not provided (16)
7	-	-	Hereditary breast ovarian cancer syndrome (7)
4	-	-	Hereditary cancer-predisposing syndrome (4)
3	-	-	Familial cancer of breast (3)
2	-	-	Breast and/or ovarian cancer (2)
2	-	-	Breast-ovarian cancer, familial, susceptibility to, 1 (2)
1	-	-	BRCA2-related cancer predisposition (1)
1	-	-	BRCA2-related disorder (2)
1	-	-	Breast carcinoma (1)
1	-	-	Carcinoma of pancreas (1)
1	-	-	Medulloblastoma;C0346153:Familial cancer of breast;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C2931456:Familial prostate cancer;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 (1)
-	-	-	Hereditary breast ovarian cancer syndrome;C1838457:Fanconi anemia complementation group D1 (1)
-	-	-	Neoplasm (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.51
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs80359306; hg19: chr13-32907420; COSMIC: COSV66455573; COSMIC: COSV66455573;