rs587781536

Positions:

• chr13-32339945-G-A
• chr13-32339945-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000059.4(BRCA2):​c.5590G>A​(p.Asp1864Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000344 in 1,454,548 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1864G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1
• Conservation: PhyloP100: 0.600

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]

BRCA2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35263932).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.5590G>A	p.Asp1864Asn	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.5590G>A	p.Asp1864Asn	missense_variant	11/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.5221G>A	p.Asp1741Asn	missense_variant	11/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.5590G>A		non_coding_transcript_exon_variant	10/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000122 AC: 3 AN: 246000 Hom.: 0 AF XY: 0.0000150 AC XY: 2 AN XY: 132956

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000110

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1454548 Hom.: 0 Cov.: 45 AF XY: 0.00000553 AC XY: 4 AN XY: 722842

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 14, 2022	This missense variant replaces aspartic acid with asparagine at codon 1864 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with breast or ovarian cancer (PMID: 26852015, 27257965, 28111427, 30725392, 31161121, 33078592, 35402282), an individual affected with esophageal cancer (PMID: 22126563), and two individuals affected with colorectal cancer (PMID: 31428572). In a large breast cancer case-control meta analysis, this variant was reported in 3/60466 cases and 2/53461 unaffected controls; (OR=1.326 (95%CI 0.222 to 7.938); Leiden Open Variation Database DB-ID BRCA2_006877 (PMID: 33471991)). This variant has been identified in 3/246000 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	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). -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 22, 2024	The p.D1864N variant (also known as c.5590G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 5590. The aspartic acid at codon 1864 is replaced by asparagine, an amino acid with highly similar properties. This variant was identified in a 66-year-old Chinese male diagnosed with with esophageal squamous cell carcinoma who had no family history of cancer but did have a personal history of tobacco use (Zhong L et al. Asian Pac. J. Cancer Prev. 2011;12:1771-6). This variant was also identified in multiple individuals of Asian descent diagnosed with breast and/or ovarian cancer (Cao WM et al. BMC Cancer. 2016 Feb;16:64; Zhong X et al. PLoS ONE. 2016 Jun;11:e0156789; Kim HN et al. Chonnam Med J, 2019 May;55:99-103; Zhunussova G et al. Front Oncol, 2019 Aug;9:673; Abdel-Razeq H et al. Front Oncol, 2022 Mar;12:673094). 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jun 27, 2022

Variant summary: BRCA2 c.5590G>A (p.Asp1864Asn) results in a conservative amino acid change located in the BRCA2 repeat (IPR002093) of 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 1.9e-05 in 268772 control chromosomes (gnomAD, Dong_2021). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5590G>A has been reported in the literature in individuals affected with esophageal cancer (Zhong_2011), and Breast/Ovarian cancer (Zhong_2016, Cao_2016, Park_2017, So_2019, Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A multi-factorial analysis of ethnic Koreans by Lee_2018 produced a combined likelihood ratio of 0.023, leading the authors to conclude the variant is "likely benign". To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters have assessed the variant since 2014: all have classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Breast neoplasm Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University

Nov 01, 2015

- -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2024

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1864 of the BRCA2 protein (p.Asp1864Asn). This variant is present in population databases (rs587781536, gnomAD 0.01%). This missense change has been observed in individual(s) with breast and/or ovarian cancer and in an individual with esophageal squamous cell carcinoma and esophageal squamous cell carcinoma (PMID: 22126563, 26852015, 27257965, 30415210, 30725392, 31161121, 31907386). ClinVar contains an entry for this variant (Variation ID: 141155). 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 with a negative predictive value of 95%. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	15
DANN	Uncertain	0.99
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.68	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.35	T;T
MetaSVM	Benign	-0.95	T
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.5	N;N
REVEL	Benign	0.099
Sift	Uncertain	0.026	D;D
Sift4G	Uncertain	0.052	T;T
Vest4		0.67
MutPred		0.37		Gain of MoRF binding (P = 0.0435);Gain of MoRF binding (P = 0.0435);
MVP		0.87
MPC		0.020
ClinPred		0.071	T
GERP RS		3.0
gMVP		0.082

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: rs587781536; hg19: chr13-32914082; COSMIC: COSV105932241;