rs398122710

Positions:

• chr13-32371100-G-A
• chr13-32371100-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_000059.4(BRCA2):​c.8632G>A​(p.Glu2878Lys) 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 benign outcome for this variant. 3/3 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 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 U:2
• Conservation: PhyloP100: 9.12

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 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-32371100-G-A is Pathogenic according to our data. Variant chr13-32371100-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 91730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-32371100-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.8632G>A	p.Glu2878Lys	missense_variant, splice_region_variant	20/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.8632G>A	p.Glu2878Lys	missense_variant, splice_region_variant	20/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.8263G>A	p.Glu2755Lys	missense_variant, splice_region_variant	20/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*690G>A		splice_region_variant, non_coding_transcript_exon_variant	19/26	2		ENSP00000506251.1
BRCA2	ENST00000614259	n.*690G>A		3_prime_UTR_variant	19/25	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 21, 2023	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2878 of the BRCA2 protein (p.Glu2878Lys). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 27257965, 30702160, 35418818). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 91730). 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 20 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 27, 2024	Variant summary: BRCA2 c.8632G>A (p.Glu2878Lys) results in a conservative amino acid change located in the BRCA2, OB2 domain (IPR048262) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes/weakens the canonical 5' splicing donor site. Further, 2 independent clinical laboratories with established RNA assays reported that this variant causes skipping of exon 20 (NMD predicted) and/or aberrant splicing (Invitae, Ambry Genetics; ClinVar). The variant was absent in 250782 control chromosomes. c.8632G>A has been reported in the literature in the heterozygous state in multiple individuals affected with clinical features of Hereditary Breast And Ovarian Cancer Syndrome (example, Zhong_2016, Bhaskaran_2019, Gao_2020, Ercoskun_2022, DiRado_2023, Zhang_2022). These reports suggest the variant may be associated with BRCA2-related conditions. The following publications have been ascertained in the context of this evaluation (PMID: 30702160, 38136276, 35418818, 31825140, 35918668, 27257965). ClinVar contains an entry for this variant (Variation ID: 91730). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Breast neoplasm Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University

Nov 01, 2015

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Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 12, 2024

The c.8632G>A variant (also known as p.E2878K), located in coding exon 19 of the BRCA2 gene, results from a G to A substitution at nucleotide position 8632. The amino acid change results in glutamic acid to lysine at codon 2878, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 19, which makes it likely to have some effect on normal mRNA splicing. This variant has been reported in the literature in several individuals from breast and ovarian cancer cohorts (Bhaskaran SP et al. Int J Cancer, 2019 08;145:962-973; Zhong X et al. PLoS One, 2016 Jun;11:e0156789; Ercoskun P et al. Mol Syndromol. 2022 Feb;13(2):123-131; Zhang Y et al. BMC Cancer, 2022 Aug;22:842; Di Rado S et al. Cancers (Basel), 2023 Dec;15). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1

Uncertain significance, flagged submission

clinical testing

Sharing Clinical Reports Project (SCRP)

Nov 27, 2007

- -

Familial cancer of breast Uncertain:1

Uncertain significance, flagged submission

literature only

Center for Precision Medicine, Meizhou People's Hospital

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-0.42	T
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.97	N;N
REVEL	Benign	0.20
Sift	Benign	0.049	D;D
Sift4G	Benign	0.12	T;T
Vest4		0.23
MutPred		0.34		Gain of ubiquitination at E2878 (P = 0.0025);Gain of ubiquitination at E2878 (P = 0.0025);
MVP		0.90
MPC		0.12
ClinPred		0.96	D
GERP RS		5.3
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.72		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.34		Position offset: 17
DS_DL_spliceai		0.72		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs398122710; hg19: chr13-32945237; COSMIC: COSV66462122;