13-32344582-T-G

Position:

• chr13-32344582-T-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000059.4(BRCA2):​c.6866T>G​(p.Leu2289Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L2289L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 5.79

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 11 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 13-32344582-T-G is Pathogenic according to our data. Variant chr13-32344582-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 491310.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.6866T>G	p.Leu2289Ter	stop_gained	12/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.6866T>G	p.Leu2289Ter	stop_gained	12/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 28, 2020	This variant alters 1 nucleotide in exon 12 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Loss of BRCA2 function is a known mechanism of disease. This variant has been reported in an individual affected with breast cancer (PMID: 28831036). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). It has been shown that a transcript lacking exon 12 (delEx12) is detected at low levels (10-20%) in healthy individuals (PMID: 19795481, 32046981). This delEx12 transcript has shown varying levels of BRCA2 activity in BRCA2-null mouse embryonic stem cells (PMID: 19795481, 32046981). Of note, two of 11 truncation variants occurring in exon 12 have been shown to increase the delEx12 transcript levels to ~50% of total transcripts in the cells derived from two carriers (PMID: 32046981). However, family studies did not show a correlation of this observation with clinical outcome, and the delEx12 transcript-inducing variants were observed in multiple individuals affected with breast cancer (PMID: 32046981). In summary, limited data suggest that the deleterious effects of certain truncation variants occurring in exon 12 may be alleviated due to the induction of delEx12 transcript. However, the clinical relevance of this observation is not clearly established. Although additional studies are necessary to determine the role of this c.6849del variant in disease conclusively, the available evidence indicates that this variant is likely to result in the loss of BRCA2 function. Therefore, this variant is classified as Likely Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 03, 2018	The p.L2289* variant (also known as c.6866T>G), located in coding exon 11 of the BRCA2 gene, results from a T to G substitution at nucleotide position 6866. This changes the amino acid from a leucine to a stop codon within coding exon 11 (also known as exon 12) which is skipped in one of the natural in-frame minor isoforms expressed in normal individuals (known in the literature as BRCA2 delta 12) (Fackenthal J et al. J Med Genet. 2016 Aug; 53(8):548-58). In one study, BRCA2 exon 12 has been shown to be functionally redundant using mouse embryonic stem cells (Li L et al. Hum Mutat. 2009 Nov; 30(11):1543-50). Although alterations that result in premature protein truncation are typically deleterious in nature, protein truncating alterations that occur in exons that are skipped in naturally occurring in-frame minor isoforms have an uncertain impact on pathogenicity since it is possible that the naturally occurring isoform that lacks coding exon 11 may be partially functional. As such, the clinical significance of this alteration remains unclear. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 09, 2021

Variant summary: BRCA2 c.6866T>G (p.Leu2289X) 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 was absent in 248798 control chromosomes (gnomAD). To our knowledge, no occurrence of c.6866T>G in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	41
DANN	Uncertain	0.99
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.97	D
MutationTaster	Benign	1.0	A;A
Vest4		0.92
GERP RS		5.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1555285146; hg19: chr13-32918719;