rs80358603

chr13-32325112-G-Achr13-32325112-G-Cchr13-32325112-G-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.353G>A(p.Arg118His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000218 in 1,607,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 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. R118C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:5
• Conservation: PhyloP100: -0.977

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 chr13-32325111-C-T is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.06975585).
• BP6: Variant 13-32325112-G-A is Benign according to our data. Variant chr13-32325112-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 37845.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=4}. Variant chr13-32325112-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.353G>A	p.Arg118His	missense_variant	4/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.353G>A	p.Arg118His	missense_variant	4/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152052 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

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: 0.0000319 AC: 8 AN: 251012 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135720

Gnomad AFR exome AF: 0.000123

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: 0.0000441

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000220 AC: 32 AN: 1455546 Hom.: 0 Cov.: 29 AF XY: 0.0000262 AC XY: 19 AN XY: 724478

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000376

Gnomad4 NFE exome AF: 0.0000190

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152052 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74254

Gnomad4 AFR AF: 0.0000483

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

Bravo AF: 0.0000340

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 15, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Dec 13, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2019	This variant is associated with the following publications: (PMID: 12670525, 10923033, 11948123) -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 01, 2023	Variant summary: BRCA2 c.353G>A (p.Arg118His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251012 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.353G>A has been reported in the literature as a VUS in cohorts of individuals affected with breast/ovarian cancer as well as in settings of esophageal squamous carcinoma (example, Hu_2002, Machakova_2019, Nguyen-Dumont_2020, Santonocito_2020, Ko_2020). In at-least one of these reports, a patient with esophageal squamous carcinoma also harbored a 12bp deletion at codon 174 of the TP53 gene, although the germline or somatic context of this observation was not clearly specified (example, Hu_2002). A loss of the wild-type BRCA2 allele was observed in this patient. These report(s) 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. Nine 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 (likely benign, n=4; VUS, n=5). Some submitters cite limited overlapping evidence utilized in the context of this evaluation. One submitter reports an unspecified co-occurence with a mutation in same gene (phase unknown), supporting a benign outcome. Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Feb 11, 2008	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Jan 15, 1999	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 09, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 08, 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. -

Cancer of the pancreas Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

3DMed Clinical Laboratory Inc

May 21, 2018

- -

Familial cancer of breast Benign:1

Likely benign, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Feb 09, 2024

ACMG codes applied following ENIGMA VCEP rules: BP1_STR -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	0.54
Dann	Benign	0.69
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.018	N
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.070	T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.18	N;N
REVEL	Uncertain	0.33
Sift	Benign	0.50	T;T
Sift4G	Uncertain	0.032	D;D
Vest4		0.097
MVP		0.66
MPC		0.022
ClinPred		0.0083	T
GERP RS		-4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.14

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: rs80358603; hg19: chr13-32899249; COSMIC: COSV66456384;