13-32362693-G-T

Position:

• chr13-32362693-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_000059.4(BRCA2):​c.7976G>T​(p.Arg2659Ile) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2659K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.89

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-32362693-G-A is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.941

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.7976G>T	p.Arg2659Ile	missense_variant, splice_region_variant	17/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.7976G>T	p.Arg2659Ile	missense_variant, splice_region_variant	17/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.7607G>T	p.Arg2536Ile	missense_variant, splice_region_variant	17/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*34G>T		splice_region_variant, non_coding_transcript_exon_variant	16/26	2		ENSP00000506251.1
BRCA2	ENST00000614259	n.*34G>T		3_prime_UTR_variant	16/25	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Dec 09, 2022

Variant summary: BRCA2 c.7976G>T (p.Arg2659Ile) results in a non-conservative amino acid change located in the Breast cancer type 2 susceptibility protein, helical domain (IPR015252) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251134 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.7976G>T in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Other variants at this amino acid position (c.7976G>A: p.Arg2659Lys and c.7976G>C: p.Arg2659Thr) have been reported as pathogenic but there is not enough data at this time to make any conclusions for c.7976G>T. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 14, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the c.7976G nucleotide in the BRCA2 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 12624152, 16489001, 19043619, 28339459). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 1878261). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with isoleucine, which is neutral and non-polar, at codon 2659 of the BRCA2 protein (p.Arg2659Ile). This variant also falls at the last nucleotide of exon 17, which is part of the consensus splice site for this exon. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	0.94	D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-2.1	N;N
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0070	D;D
Vest4		0.77
MutPred		0.85		Loss of MoRF binding (P = 0.0133);Loss of MoRF binding (P = 0.0133);
MVP		0.98
MPC		0.19
ClinPred		0.98	D
GERP RS		5.7
gMVP		0.84

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: 0

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-32936830;