rs80359143

chr13-32379480-G-Achr13-32379480-G-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6

The NM_000059.4(BRCA2):c.8918G>A(p.Arg2973His) variant causes a missense change. The variant allele was found at a frequency of 0.0000707 in 1,613,142 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R2973C) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000075 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:11
• Conservation: PhyloP100: 3.73

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.

• BP6: Variant 13-32379480-G-A is Benign according to our data. Variant chr13-32379480-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 38194.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=9, Uncertain_significance=3, Benign=1}. Variant chr13-32379480-G-A is described in Lovd as [Likely_benign]. Variant chr13-32379480-G-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.8918G>A	p.Arg2973His	missense_variant	22/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.8918G>A	p.Arg2973His	missense_variant	22/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152096 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000401 AC: 10 AN: 249436 Hom.: 0 AF XY: 0.0000445 AC XY: 6 AN XY: 134914

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000164

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.0000356

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000746 AC: 109 AN: 1461046 Hom.: 0 Cov.: 31 AF XY: 0.0000771 AC XY: 56 AN XY: 726788

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000757

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.0000872

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152096 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74294

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000264

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1 Benign:4

Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 20, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 04, 2024	This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease. -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Likely benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Nov 05, 2013	- -

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 10, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 04, 2020	This variant is associated with the following publications: (PMID: 29884841, 31131967, 30212499, 16284991, 22034289, 19043619, 22711857, 21702907, 20127978, 30287823) -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 16, 2022	The BRCA2 c.8918G>A; p.Arg2973His variant (rs80359143) is reported in the literature in individuals affected with breast or ovarian cancer, but without clear disease association (Alsop 2012, Fackenthal 2012, Morgan 2010, Pal 2005). This variant is also reported in ClinVar (Variation ID: 38194), and is found in the general population with an overall allele frequency of 0.0040% (10/249436 alleles) in the Genome Aggregation Database. The arginine at codon 2973 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.449). In vitro functional analyses demonstrate no effect on homology directed repair (Hart 2019, Richardson 2021). However, given the limited clinical and functional data, the significance of this variant is uncertain at this time. References: Alsop K et al. BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J Clin Oncol. 2012 Jul 20;30(21):2654-63. PMID: 22711857. Fackenthal JD et al. High prevalence of BRCA1 and BRCA2 mutations in unselected Nigerian breast cancer patients. Int J Cancer. 2012 Sep 1;131(5):1114-23. PMID: 22034289. Hart SN et al. Comprehensive annotation of BRCA1 and BRCA2 missense variants by functionally validated sequence-based computational prediction models. Genet Med. 2019 Jan;21(1):71-80. PMID: 29884841. Morgan JE et al. Genetic diagnosis of familial breast cancer using clonal sequencing. Hum Mutat. 2010 Apr;31(4):484-91. PMID: 20127978. Pal T et al. BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer. 2005 Dec 15;104(12):2807-16. PMID: 16284991. Richardson ME et al. Strong functional data for pathogenicity or neutrality classify BRCA2 DNA-binding-domain variants of uncertain significance. Am J Hum Genet. 2021 Mar 4;108(3):458-468. PMID: 33609447. -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 04, 2023	Variant summary: BRCA2 c.8918G>A (p.Arg2973His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 249436 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (4e-05 vs 0.00075), allowing no conclusion about variant significance. c.8918G>A has been reported in the literature in individuals affected with Breast and/or Ovarian Cancer (example, Alsop_2012, Fackenthal_2012, Pal_2005). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. A Japanese case-control study reported the variant as "benign" due to its presence in controls and absence in cases (Momozawa_2018). One co-occurrence with another pathogenic variant has been reported (BRCA2 c.1219_1219delC, p.Gln407Argfs, BIC), providing supporting evidence for a benign role. At least two publications report experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on HDR activity (Hart_2019, Richardson_2021). HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. This working group has recommended strong functional evidence (ACMG BS3) as sufficient weightage for categorization as likely benign (Tavtigian_2018). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as likely benign (n=5) and VUS (n=3). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 28, 2019	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	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 24, 2014	- -

Breast and/or ovarian cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Dec 08, 2016

- -

Neuroblastoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Apr 03, 2017

- -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.13
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.47	T;T
MetaSVM	Uncertain	0.10	D
MutationTaster	Benign	0.72	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.5	N;N
REVEL	Uncertain	0.45
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.056	T;T
Vest4		0.34
MVP		0.95
MPC		0.18
ClinPred		0.49	T
GERP RS		5.5
gMVP		0.47

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: rs80359143; hg19: chr13-32953617; COSMIC: COSV66461060; COSMIC: COSV66461060;