rs864622735

Positions:

• chr13-32379463-AACCGTGTGGAAG-ATCCC

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1 PS1 PM2 PP5_Very_Strong

The NM_000059.4(BRCA2):​c.8902_8913delACCGTGTGGAAGinsTCCC​(p.Thr2968fs) variant causes a frameshift, missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd. Synonymous variant affecting the same amino acid position (i.e. T2968T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 frameshift, missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 7.39

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 22 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS1: Transcript NM_000059.4 (BRCA2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-32379464-ACCGTGTGGAAG-TCCC is Pathogenic according to our data. Variant chr13-32379464-ACCGTGTGGAAG-TCCC is described in ClinVar as [Pathogenic]. Clinvar id is 221071.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.8902_8913delACCGTGTGGAAGinsTCCC	p.Thr2968fs	frameshift_variant, missense_variant	22/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.8902_8913delACCGTGTGGAAGinsTCCC	p.Thr2968fs	frameshift_variant, missense_variant	22/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.8533_8544delACCGTGTGGAAGinsTCCC	p.Thr2845fs	frameshift_variant, missense_variant	22/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*960_*971delACCGTGTGGAAGinsTCCC		non_coding_transcript_exon_variant	21/26	2		ENSP00000506251.1
BRCA2	ENST00000614259	n.*960_*971delACCGTGTGGAAGinsTCCC		3_prime_UTR_variant	21/25	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

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)

Apr 22, 2016

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

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 06, 2022

The c.8902_8913del12insTCCC pathogenic mutation, located in coding exon 21 of the BRCA2 gene, results from the deletion of 12 nucleotides and insertion of 4 nucleotides causing a translational frameshift with a predicted alternate stop codon (p.T2968Sfs*47). 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. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 29, 2022

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This sequence change creates a premature translational stop signal (p.Thr2968Serfs*47) 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). -

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: rs864622735; hg19: chr13-32953601;