chr13-32362593-T-C

Position:

• chr13-32362593-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000059.4(BRCA2):​c.7876T>C​(p.Trp2626Arg) variant causes a missense 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. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W2626C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.93

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 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-32362595-G-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 13-32362593-T-C is Pathogenic according to our data. Variant chr13-32362593-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 429208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.7876T>C	p.Trp2626Arg	missense_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.7876T>C	p.Trp2626Arg	missense_variant	17/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.7507T>C	p.Trp2503Arg	missense_variant	17/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.7884T>C		non_coding_transcript_exon_variant	16/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 30, 2014

This variant is denoted BRCA2 c.7876T>C at the cDNA level, p.Trp2626Arg (W2626R) at the protein level, and results in the change of a Tryptophan to an Arginine (TGG>CGG) in exon 17. This variant was observed in at least one individual with breast cancer (Kim 2006). BRCA2 Trp2626Arg was not observed in approximately 6,500 individuals of European and African American ancestry in an external variant database, indicating it is not a common benign variant in these populations. Since Tryptophan and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Trp2626Arg alters a position that is conserved across species and is located in the DNA-binding domain (Borg 2010). In silico analyses predict that this variant is probably damaging to protein structure and function. Another non-conservative missense substitution at this position, Trp2626Cys, has been observed in at least three women with a history of breast cancer and one child with Fanconi Anemia, was strongly predicted by Lindor et al. (2012) to be pathogenic based on tumor pathology, and has been showed to have impaired homologous recombination (Barber 2005, Borg 2010, Biswas 2011, Capanu 2011, Meyer 2012, Guidugli 2013). However, Biswas et al. (2011) found Trp2626Cys was able to rescue embryonic stem cell lethality although the rescued cells had reduced viability and Pruss et al. (2014) suggested that Trp2626Cys may be a lower penetrance or hypomorphic allele based on a clinical history weighting algorithm. Based on currently available information, we consider BRCA2 Trp2626Arg to be an expected pathogenic variant. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 12, 2020

The p.W2626R pathogenic mutation (also known as c.7876T>C), located in coding exon 16 of the BRCA2 gene, results from a T to C substitution at nucleotide position 7876. The tryptophan at codon 2626 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in two Korean individuals diagnosed with sporadic breast cancer and was not detected in 167 controls (Han SH et al. Clin. Genet. 2006 Dec; 70(6):496-501). A close-match alteration at this codon, p.W2626C, has been reported in individuals with hereditary breast and ovarian cancer syndrome and Fanconi Anemia and was found deleterious in numerous functional assays; however one study found the close-match variant to be hypomorphic (Borg A et al. Hum. Mutat. 2010 Mar;31:E1200-40; Konecny M et al. Breast Cancer Res.Treat. 2011 Feb;126:119-30; Wagner JE et al. Blood. 2004 Apr;103:3226-9; Guidugli L et al. Am. J. Hum. Genet. 2018 Jan; Pruss D et al. Breast Cancer Res. Treat., 2014 Aug;147:119-32). This alteration is deleterious in a homology directed repair assay (Hart SN et al. Genet. Med. 2019 01;21:71-80). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Yang H et al. Science. 2002 Sep;297:1837-48). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this alteration is interpreted as a disease-causing mutation. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 29, 2022

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Trp2626 amino acid residue in BRCA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16115142, 20104584, 21138478, 21719596, 25085752). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33609447) indicates that this missense variant is expected to disrupt BRCA2 function. ClinVar contains an entry for this variant (Variation ID: 429208). This variant is also known as 8104T>C. This missense change has been observed in individual(s) with breast cancer (PMID: 17100994, 34645131). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 2626 of the BRCA2 protein (p.Trp2626Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.7	D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.90
MutPred		0.91		Loss of ubiquitination at K2630 (P = 0.0449);Loss of ubiquitination at K2630 (P = 0.0449);
MVP		1.0
MPC		0.19
ClinPred		1.0	D
GERP RS		5.7
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1060502459; hg19: chr13-32936730;