13-32340069-A-G

Position:

• chr13-32340069-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_000059.4(BRCA2):​c.5714A>G​(p.His1905Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,794 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).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:4
• Conservation: PhyloP100: 0.719

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 -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14637172).
• BP6: Variant 13-32340069-A-G is Benign according to our data. Variant chr13-32340069-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 51913.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.5714A>G	p.His1905Arg	missense_variant	11/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.5714A>G	p.His1905Arg	missense_variant	11/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152224 Hom.: 0 Cov.: 33

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461570 Hom.: 0 Cov.: 45 AF XY: 0.00000413 AC XY: 3 AN XY: 727086

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152224 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74368

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: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000333 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 23, 2024	The p.H1905R variant (also known as c.5714A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 5714. The histidine at codon 1905 is replaced by arginine, an amino acid with highly similar properties. This alteration was observed in 0/7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.00009 in 11,241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This alteration was also detected in 2/11,386 Chinese Han individuals undergoing routine health examinations and screened for BRCA1/2 alterations (Dong H et al. J Med Genet, 2021 08;58:565-569). Authors of one study classified this variant as likely not pathogenic based on a combination of multifactorial likelihood analyses and an in vitro splicing assay and another study using four in silico prediction tools found this variant to be tolerated in all models (Whiley PJ et al. PLoS One, 2014 Jan;9:e86836; Ernst C et al. BMC Med Genomics, 2018 03;11:35). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 19, 2016	- -
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). -

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

Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 17, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 15, 2023

Variant summary: BRCA2 c.5714A>G (p.His1905Arg) 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 1.1e-05 in 271460 control chromosomes (gnomAD and publications).The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5714A>G has been identified as a VUS in a screen of healthy individuals from a Han Chinese population (found in 2/9,331 individuals) and in a case-control study of Japanese breast cancer patients where it was not found in cases but was found in controls (Momozawa_2018, Dong_2020). To our knowledge, no occurrence of in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome has been reported in the literature. The variant has been classified as IARC Class 2 (likely not pathogenic) based on multifactorial likelihood analysis (Whiley_2014) however, this has yet to be confirmed by functional studies. The following publications have been ascertained in the context of this evaluation (PMID: 24489791, 30287823, 32467295). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments (likely benign n=3, VUS n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 22, 2018

This variant is denoted BRCA2 c.5714A>G at the cDNA level, p.His1905Arg (H1905R) at the protein level, and results in the change of a Histidine to an Arginine (CAT>CGT). Using alternate nomenclature, this variant would be defined as BRCA2 5942A>G. BRCA2 His1905Arg was classified as likely not pathogenic by a multifactorial likelihood analysis utilizing bioinformatic models and segregation data (Whiley 2014). BRCA2 His1905Arg was not observed in large population databases (Lek 2016). Since Histidine and Arginine share similar properties, this is considered a conservative amino acid substitution. BRCA2 His1905Arg is located in the RAD51 binding domain (Roy 2012). In silico analysis, which includes protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 His1905Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	4.1
DANN	Benign	0.44
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.11	N
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.2	N;N
REVEL	Uncertain	0.30
Sift	Benign	0.35	T;T
Sift4G	Benign	0.37	T;T
Vest4		0.26
MVP		0.80
MPC		0.022
ClinPred		0.20	T
GERP RS		3.0
gMVP		0.097

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: rs80358796; hg19: chr13-32914206;