rs80358567

chr13-32325081-A-Cchr13-32325081-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_000059.4(BRCA2):c.322A>C(p.Asn108His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000515 in 1,574,284 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N108S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign reviewed by expert panel U:4 B:11
• Conservation: PhyloP100: 0.691

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.027701616).
• BP6: Variant 13-32325081-A-C is Benign according to our data. Variant chr13-32325081-A-C is described in ClinVar as [Benign]. Clinvar id is 51428.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.322A>C	p.Asn108His	missense_variant	4/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.322A>C	p.Asn108His	missense_variant	4/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.000315 AC: 48 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000679 AC: 17 AN: 250526 Hom.: 0 AF XY: 0.0000517 AC XY: 7 AN XY: 135448

Gnomad AFR exome AF: 0.00105

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000225 AC: 32 AN: 1421942 Hom.: 0 Cov.: 27 AF XY: 0.0000211 AC XY: 15 AN XY: 709750

Gnomad4 AFR exome AF: 0.000889

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.0000339

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152342 Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74496

Gnomad4 AFR AF: 0.00115

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000226 Hom.: 0

Bravo AF: 0.000344

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000741 AC: 9

ClinVar

Significance: Benign

Submissions summary: Uncertain:4 Benign:11

Revision: reviewed by expert panel

Submissions by phenotype

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

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Feb 20, 2004	- -
Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Jun 18, 2019	Variant allele has low bioinformatic likelihood to encode a missense alteration affecting protein function (Missense prior probability 0.02; http://priors.hci.utah.edu/PRIORS/), AND low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/), AND minor allele frequency 0.00136 (African), derived from gnomAD v2.1.1 non-cancer (2019-05-13). -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jul 07, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Feb 27, 2023	- -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 13, 2020	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	Nov 02, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 30, 2016	- -

Hereditary breast ovarian cancer syndrome Benign:3

Likely benign, criteria provided, single submitter	research	Genetics Program, Instituto Nacional de Cancer	Nov 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Nov 16, 2021	- -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 13, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 23, 2020	This variant is associated with the following publications: (PMID: 12491487, 11030417, 23231788, 12955716, 16234499, 9971877, 22476429, 26580448) -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 14, 2021	Variant summary: BRCA2 c.322A>C (p.Asn108His) 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 7.2e-05 in 251048 control chromosomes, predominantly at a frequency of 0.001 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00075), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.322A>C has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Wagner_1999, Gao_2000, Diez_2003, Nanda_2005, Lu_2012). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Co-occurrences with pathogenic variants have been observed via internal testing [BRCA1 c.3748G>T, p.Glu1250X; BRCA1 c.(4185+1_4186-1)_(4357+1_4358-1)dup], providing supporting evidence for a benign role. Nine submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014. Five ClinVar submitters have cited the variant as likely benign, 2 submitters have cited it as variant of unknown significance and 2 submitters (including an expert panel, ENIGMA) have cited is as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 28, 2021	- -

BRCA2-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 04, 2022

The BRCA2 c.322A>C variant is predicted to result in the amino acid substitution p.Asn108His. This variant has been reported in multiple individuals with breast and/or ovarian cancer (Wagner et al. 1999. PubMed ID: 9971877, Gao et al. 2000. PubMed ID: 11030417, Díez et al. 2003. PubMed ID: 12955716, Nanda et al. 2005. PubMed ID: 16234499, Lu et al. 2012. PubMed ID: 22476429); however, no evidence was provided to support its pathogenicity. This variant is reported in 0.13% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-32899218-A-C) and has interpretations in ClinVar ranging from benign to a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/51428/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	13
Dann	Benign	0.95
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.35	N
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.028	T;T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.64	N;N
REVEL	Benign	0.26
Sift	Benign	0.11	T;T
Sift4G	Uncertain	0.040	D;D
Vest4		0.18
MVP		0.86
MPC		0.021
ClinPred		0.012	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs80358567; hg19: chr13-32899218;