rs28897718

chr13-32337312-A-Gchr13-32337312-A-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM5 BP4_Moderate BP6

The NM_000059.4(BRCA2):c.2957A>G(p.Asn986Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000843 in 1,613,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign 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. N986D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000091 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:8
• Conservation: PhyloP100: 0.0760

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 Likely_benign. Variant got -1 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-32337311-AAT-AG is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.15537965).
• BP6: Variant 13-32337312-A-G is Benign according to our data. Variant chr13-32337312-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 51377.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=6, Likely_benign=5}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.2957A>G	p.Asn986Ser	missense_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.2957A>G	p.Asn986Ser	missense_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152260 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000520 AC: 13 AN: 249782 Hom.: 0 AF XY: 0.0000739 AC XY: 10 AN XY: 135316

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000910 AC: 133 AN: 1460894 Hom.: 0 Cov.: 33 AF XY: 0.000100 AC XY: 73 AN XY: 726714

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000115

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152260 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74396

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000225 Hom.: 0

Bravo AF: 0.0000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 07, 2016	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Dec 21, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 25, 2018	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	University of Washington Department of Laboratory Medicine, University of Washington	Mar 23, 2023	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 30, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2020	This variant is associated with the following publications: (PMID: 20104584, 25682074, 23929434, 27882345, 21520273) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 25, 2019	- -

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

Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 01, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 19, 2016	- -
Benign, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 07, 2019	The BRCA2 c.2957A>G; p.Asn986Ser variant (rs28897718) is reported in the literature in several individuals affected with breast cancer, although its clinical significance was not determined in these studies (Borg 2010, Wong-Brown 2015). This variant is reported in ClinVar (Variation ID: 51377), and it is found in the non-Finnish European population with an overall allele frequency of 0.01% (13/128448 alleles) in the Genome Aggregation Database. The asparagine at codon 986 is moderately conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, given the lack of clinical and functional data, the significance of the p.Asn986Ser variant is uncertain at this time. References: Borg A et al. Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. Hum Mutat. 2010 Mar;31(3):E1200-40. Wong-Brown MW et al. Prevalence of BRCA1 and BRCA2 germline mutations in patients with triple-negative breast cancer. Breast Cancer Res Treat. 2015 Feb;150(1):71-80. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 31, 2023	Variant summary: BRCA2 c.2957A>G (p.Asn986Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 249782 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (5.2e-05 vs 0.00075), allowing no conclusion about variant significance. c.2957A>G has been reported in the literature in individuals affected with Breast Cancer (example, Borg 2008, Capanu_2011, Wong-Brown 2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant(s) have been reported in the BIC database (BRCA2 c.2808_2811delACAA, p.Lys936_Gln937?fs), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function (Biswas_2020). These results showed no damaging effect of this variant based on probability of impact on function (PIF) of variants based on cell survival (HAT) and drug sensitivity (DS) assay results individually and combined (HAT +DS). The following publications have been ascertained in the context of this evaluation (PMID: 33293522, 20104584, 21520273, 23929434, 25682074). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=5; VUS, n=5). Based on the evidence outlined above, the variant was classified as likely benign. -

Breast and/or ovarian cancer Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Sep 19, 2002

- -

BRCA2-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 09, 2024

The BRCA2 c.2957A>G variant is predicted to result in the amino acid substitution p.Asn986Ser. This variant has been documented in patients with breast cancer from large cohort studies (Supp. Table S3, Borg et al. 2010. PubMed ID: 20104584; Supplementary Table, Capanu et al. 2011. PubMed ID: 21520273; Supplementary Table 2, Wong-Brown et al. 2015. PubMed ID: 25682074). However, further clinical or functional evidence was not provided to assess the pathogenicity of this variant. This variant is reported in 0.010% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations regarding its pathogenicity ranging from benign to uncertain in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/51377). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	1.2
Dann	Benign	0.96
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.22	N
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Benign	0.052
Sift	Benign	0.10	T;T
Sift4G	Benign	0.30	T;T
Vest4		0.34
MVP		0.83
MPC		0.023
ClinPred		0.12	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.28

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: rs28897718; hg19: chr13-32911449;