13-32362698-G-T

Position:

• chr13-32362698-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_000059.4(BRCA2):​c.7976+5G>T variant causes a splice donor 5th base, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 splice_donor_5th_base, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 U:1
• Conservation: PhyloP100: 4.50

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 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 13-32362698-G-T is Pathogenic according to our data. Variant chr13-32362698-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 462463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.7976+5G>T		splice_donor_5th_base_variant, intron_variant		ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.7976+5G>T		splice_donor_5th_base_variant, intron_variant		5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 25, 2023	The c.7976+5G>T intronic variant results from a G to T substitution 5 nucleotides after coding exon 16 in the BRCA2 gene. This variant segregated with breast cancer in three families (Montalban G et al. Hum. Mutat., 2018 Sep;39:1155-1160; Ambry internal data), and RNA analyses on several probands demonstrated that it results in skipping of coding exon 16 (also referred to as exon 17), which is located in a domain that is important for protein function (Ambry internal data; Montalban G et al. Hum. Mutat., 2018 Sep;39:1155-1160). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 18, 2021	This variant causes a G to T nucleotide substitution at the +5 position of intron 17 of the BRCA2 gene. This variant is also known as IVS17+5G>T in the literature. Functional RNA studies have shown that this variant causes in-frame skipping of exon 17 (PMID: 29969168, 31191615) resulting in a non-functional protein (PMID: 15695382, 18451181). This variant has been reported in 5 individuals who were affected with breast and/or ovarian cancer from 3 families (PMID: 29969168). This variant has not been identified 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:2

Pathogenic, no assertion criteria provided	research	Hereditary Cancer Genetics group, Vall d'Hebron Institute of Oncology	Mar 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 01, 2022	ClinVar contains an entry for this variant (Variation ID: 462463). This variant has been observed in individual(s) with breast and/or ovarian cancer (PMID: 29969168). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 17 of the BRCA2 gene. It does not directly change the encoded amino acid sequence of the BRCA2 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant disrupts the p.His2623 amino acid residue in BRCA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26023681, 29394989, 31409081, 32444794). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 17, but is expected to preserve the integrity of the reading-frame (PMID: 29969168). For these reasons, this variant has been classified as Pathogenic. -

not provided Uncertain:1

Uncertain significance, flagged submission

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Aug 16, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Benign	0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.89		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.89		Position offset: -5

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

Publications

LitVar

Other links and lift over

dbSNP: rs786201180; hg19: chr13-32936835;