13-32339555-GAAAAA-GGAAAAG

Position:

• chr13-32339555-GAAAAA-GGAAAAG

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.5201_5205delAAAAAinsGAAAAG​(p.Glu1734fs) variant causes a frameshift, missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BRCA2 NM_000059.4 frameshift, missense
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 3.06

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 13-32339556-AAAAA-GAAAAG is Pathogenic according to our data. Variant chr13-32339556-AAAAA-GAAAAG is described in ClinVar as [Pathogenic]. Clinvar id is 438988.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.5201_5205delAAAAAinsGAAAAG	p.Glu1734fs	frameshift_variant, missense_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.5201_5205delAAAAAinsGAAAAG	p.Glu1734fs	frameshift_variant, missense_variant	11/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.4832_4836delAAAAAinsGAAAAG	p.Glu1611fs	frameshift_variant, missense_variant	11/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.5201_5205delAAAAAinsGAAAAG		non_coding_transcript_exon_variant	10/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 20, 2018	Variant summary: BRCA2 c.5201_5205delinsGAAAAG (p.Glu1734GlyfsX9) 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 (eg. c.5213_5216delCTTA, p.Thr1738fsX2; c.5217_5223delTTTAAGT, p.Tyr1739X; c.5238dupT, p.Asn1747X). The variant was absent in 273414 control chromosomes (gnomAD). To our knowledge, no occurrence of c.5201_5205delinsGAAAAG in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Jun 04, 2021	The BRCA2 c.5201_5205delinsGAAAAG (p.Glu1734Glyfs*9) change causes a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of the protein due to nonsense mediated decay (PVS1). This variant is absent in gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/). It is also absent in the FLOSSIES database which contains genetic variants from women older than 70 years of age who have never had cancer (https://whi.color.com/). To our knowledge, this variant has not been reported in individuals affected with hereditary breast and ovarian cancer or Fanconi anemia. However, truncating variants downstream of the p.Glu1734fs change have been reported in individuals with breast and/or ovarian cancer and are known to be pathogenic. In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria: PVS1, PM2_Supporting. -

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:1

Pathogenic, reviewed by expert panel

curation

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Dec 15, 2017

Variant allele predicted to encode a truncated non-functional protein. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Feb 11, 2017

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 12, 2023

The c.5201_5205delAAAAAinsGAAAAG pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from the deletion of 5 nucleotides and insertion of 6 nucleotides causing a translational frameshift with a predicted alternate stop codon (p.E1734Gfs*9). 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs483353082; hg19: chr13-32913693;