rs373400041

chr13-32333241-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000059.4(BRCA2):c.1763A>G(p.Asn588Ser) 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 1,612,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. N588D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:8 B:2
• Conservation: PhyloP100: 0.829

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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11630142).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.1763A>G	p.Asn588Ser	missense_variant	10/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.1763A>G	p.Asn588Ser	missense_variant	10/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 249674 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 135124

Gnomad AFR exome AF: 0.0000627

Gnomad AMR exome AF: 0.0000874

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: 0.00000342 AC: 5 AN: 1460284 Hom.: 0 Cov.: 35 AF XY: 0.00000413 AC XY: 3 AN XY: 726438

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000673

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000656 AC: 1 AN: 152332 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74488

Gnomad4 AFR AF: 0.0000241

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

Bravo AF: 0.00000756

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:8 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 23, 2023	This missense variant replaces asparagine with serine at codon 588 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may impact RNA splicing. RNA studies have show that this variant results an in-frame deletion of the last 147 nucleotides from exon 10 of the BRCA2 gene (PMID: 20215541, 21735045). However, the impact on RNA splicing may be partial and the clinical relevance of this observation is not known. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 15937982, 16758124, 20215541, 21735045, 33471991; Leiden Open Variation Database DB-ID BRCA2_000486). This variant has also been identified in 4/249674 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 31, 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). -

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

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 02, 2023	This missense variant replaces asparagine with serine at codon 588 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may impact RNA splicing. RNA studies have show that this variant results an in-frame deletion of the last 147 nucleotides from exon 10 of the BRCA2 gene (PMID: 20215541, 21735045). However, the impact on RNA splicing may be partial and the clinical relevance of this observation is not known. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 15937982, 16758124, 20215541, 21735045, 33471991; Leiden Open Variation Database DB-ID BRCA2_000486). This variant has also been identified in 4/249674 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Pathogenic, flagged submission	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 15, 2019	Variant summary: BRCA2 c.1763A>G (p.Asn588Ser) results in a 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. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a cryptic 5 donor site. These predictions have been confirmed by functional studies which show the variant creates a new cryptic donor site, which leads to an alternative transcript consisting of an in-frame deletion of 147 nucleotides (r.1763_1909del) that, in turn, produces an in-frame deletion of 49 amino acids with the insertion of a serine. However, due to the in-frame nature of this alternate splicing, it was considered a VUS (Menendez_2012, Sanz_2010). The variant allele was found at a frequency of 1.6e-05 in 249674 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1763A>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Rebbeck_2018, Menendez_2012, Sanz_2010, Velasco_2005). One published study reports lack of co-segregation of the variant with the disease (affected mother did not carry the variant; Menendez_2012). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. A co-occurrence with a pathogenic variant has been reported following internal testing (LabCorp; BRCA2 c.658_659delGT, p.Val220fsX4), providing supporting evidence for a benign role. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance (2x), likely benign (1x) and once as pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

Breast neoplasm Uncertain:1

Uncertain significance, criteria provided, single submitter

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

Low GERP score may suggest that this variant may belong in a lower pathogenicity class -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

May 08, 2023

The frequency of this variant in the general population, 0.000087 (3/34322 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals and families with breast and/or ovarian cancer (PMIDs: 29446198 (2018), 21735045 (2012), and 20215541 (2010)), as well as in a breast cancer case in a large scale breast cancer association study (PMID: 33471991 (2021)). The variant was reported to not segregate with disease in a family with early onset breast cancer (PMID: 21735045 (2012)). An in vitro functional study indicated that the variant led to an in-frame deletion of 49 amino acids that are not in a known functional domain of the BRCA2 protein (PMID: 20215541 (2010)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Additional analysis using software algorithms for the prediction of the effect of nucleotide changes on BRCA2 mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites . Based on the available information, we are unable to determine the clinical significance of this variant. -

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 01, 2019

- -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 04, 2023

ClinVar contains an entry for this variant (Variation ID: 51186). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Studies have shown that this missense change is associated with altered splicing resulting in unknown protein product impact (PMID: 20215541, 21735045; Invitae). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function. This variant is also known as 1991A>G. This missense change has been observed in individual(s) with breast cancer (PMID: 20215541, 21735045). This variant is present in population databases (rs373400041, gnomAD 0.009%). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 588 of the BRCA2 protein (p.Asn588Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	23
Dann	Uncertain	0.99
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.70	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.36	N;N
REVEL	Benign	0.083
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.019	D;D
Vest4		0.17
MVP		0.85
MPC		0.021
ClinPred		0.079	T
GERP RS		0.56
gMVP		0.093

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.83		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.83		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs373400041; hg19: chr13-32907378;