rs80359077

chr13-32370426-G-Achr13-32370426-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM5 PP3 BP6

The NM_000059.4(BRCA2):c.8356G>A(p.Ala2786Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2786D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:7
• Conservation: PhyloP100: 9.94

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 15 uncertain in NM_000059.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-32370426-G-C is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.749
• BP6: Variant 13-32370426-G-A is Benign according to our data. Variant chr13-32370426-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 52560.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=5}. Variant chr13-32370426-G-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.8356G>A	p.Ala2786Thr	missense_variant	19/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.8356G>A	p.Ala2786Thr	missense_variant	19/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152076 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000597 AC: 15 AN: 251430 Hom.: 1 AF XY: 0.0000442 AC XY: 6 AN XY: 135884

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000761

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461606 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727138

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152076 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74278

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ExAC AF: 0.0000576 AC: 7

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 14, 2023	In the published literature, the variant has been reported in individuals with breast and/or ovarian cancer (PMID: 28222693 (2017), 27376475 (2016), 26689913 (2015), 14973102 (2004), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). The variant has also been reported in unaffected individuals (PMID: 32467295 (2020), 28222693 (2017), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). Published functional studies have reported conflicting results on the effect of this variant on BRCA2 protein function (PMID: 33314489 (2021), 29394989 (2018)). The frequency of this variant in the general population, 0.00075 (15/19954 chromosomes in East Asian subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 11, 2019	The BRCA2 c.8356G>A; p.Ala2786Thr variant (rs80359077), also known as 8584G>A for traditional nomenclature, is reported in the literature in individuals with hereditary breast and ovarian cancer syndrome (Lai 2017, Suter 2004, Thirthagiri 2008, Wong 2015), but is also reported in healthy controls (Lai 2017). This variant is reported in ClinVar (Variation ID: 52560). It is found in the general East Asian population with an allele frequency of 0.08% (15/19954 alleles, including 1 homozygote) in the Genome Aggregation Database. The alanine at codon 2786 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Lai KN et al. Characterization of BRCA1 and BRCA2 variants in multi-ethnic Asian cohort from a Malaysian case-control study. BMC Cancer. 2017 Feb 22;17(1):149. Suter NM et al. BRCA1 and BRCA2 mutations in women from Shanghai China. Cancer Epidemiol Biomarkers Prev. 2004 Feb;13(2):181-9. Thirthagiri E et al. Evaluation of BRCA1 and BRCA2 mutations and risk-prediction models in a typical Asian country (Malaysia) with a relatively low incidence of breast cancer. Breast Cancer Res. 2008;10(4):R59. Wong ES et al. Predictive Factors for BRCA1 and BRCA2 Genetic Testing in an Asian Clinic-Based Population. PLoS One. 2015 Jul 29;10(7):e0134408. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 23, 2022	BS3_supporting -

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

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 15, 2018	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Sep 18, 2010	- -
Likely benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Jun 19, 2012	- -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 10, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 09, 2023	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 30, 2020	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 24, 2023	Variant summary: BRCA2 c.8356G>A (p.Ala2786Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251430 control chromosomes, predominantly at a frequency of 0.00076 within the East Asian subpopulation in the gnomAD database, including 1 homozygote. This frequency is higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (0.00076 vs 0.00075), suggesting it might be a benign variant primarily in the populations of East Asian origin. c.8356G>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome without strong evidence for causality (example, Kwong_2016, Schenkel_2016, Suter_2004, Thirthagiri_2008, Wong_2015), it is also reported in both breast cancer (BC) cases and in unaffected controls (Dorling_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Moreover, no significant allelic differences of this variant have been identified in large-scale Asian case-control studies: i.e. the variant was similarly present in 10/7,840 BC cases and in 11/7,928 controls (P=0.85, Sullivan_2021). In another multi-ethnic Asian case-control study, the variant was also found insignificantly in both Breast Cancer (BC) cases and healthy controls: 8/2088 (0.17%) in BC cases and 4/1448 (0.28%) in healthy controls (P=0.5, Lai_2017). Additionally, at least one publication reports experimental evidence evaluating an impact on protein function. Assays measuring cellular viability and sensitivity to DNA damaging agents in a mouse embryonic stem cellbased model showed this variant produced the same effect as WT (Sullivan_2021). The following publications have been ascertained in the context of this evaluation (PMID: 33471991, 26187060, 28222693, 27376475, 33314489, 14973102, 18627636, 26221963). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (Likely benign, n=5; VUS, n=4). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 06, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Malignant tumor of prostate Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

3DMed Clinical Laboratory Inc

Jul 17, 2017

- -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 10, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Uncertain	0.090
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Uncertain	0.61	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.2	N;N
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.011	D;D
Vest4		0.61
MutPred		0.75		Gain of relative solvent accessibility (P = 0.0215);Gain of relative solvent accessibility (P = 0.0215);
MVP		0.93
MPC		0.16
ClinPred		0.59	D
GERP RS		4.3
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs80359077; hg19: chr13-32944563;