rs80358782

Positions:

• chr13-32339967-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000059.4(BRCA2):​c.5612G>A​(p.Ser1871Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000323 in 1,610,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S1871S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:6
• Conservation: PhyloP100: 0.589

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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.038252622).
• BP6: Variant 13-32339967-G-A is Benign according to our data. Variant chr13-32339967-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 51891.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=7}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.5612G>A	p.Ser1871Asn	missense_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.5612G>A	p.Ser1871Asn	missense_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152142 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.0000324 AC: 8 AN: 247218 Hom.: 0 AF XY: 0.0000299 AC XY: 4 AN XY: 133622

Gnomad AFR exome AF: 0.000497

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1458302 Hom.: 0 Cov.: 44 AF XY: 0.0000165 AC XY: 12 AN XY: 725210

Gnomad4 AFR exome AF: 0.000632

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.0000830

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152260 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74458

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.000196

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: 0.0000984 Hom.: 0

Bravo AF: 0.000181

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Feb 20, 2004	- -
Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 22, 2008	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jul 05, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Dec 22, 2022	ACMG classification criteria: PM2 supporting, BP4 supporting -

not provided Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 24, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 27, 2017	The BRCA2 c.5612G>A; p.Ser1871Asn variant (rs80358782) has been reported in individuals with early-onset prostate cancer or breast cancer (Edwards 2003, El Saghir 2015, Lee 2008). This variant is reported multiple times in ClinVar as uncertain (Variation ID: 51891), and observed in general population databases with overall allele frequencies of 0.02 percent (1/5008 alleles, 1000 Genomes Project), and 0.006 percent (17/273156 alleles, Genome Aggregation Database). The serine at codon 1871 is weakly conserved, and computational algorithms (SIFT, PolyPhen2, MutationTaster, Prior Probabilities) predict this variant to be tolerated. However, due to the limited information regarding p.Ser1871Asn, its clinical significance in uncertain at this time. REFERENCES Link to ClinVar database for p.Ser1871Asn: https://www.ncbi.nlm.nih.gov/clinvar/variation/51891/ Edwards SM et al. Two percent of men with early-onset prostate cancer harbor germline mutations in the BRCA2 gene. Am J Hum Genet. 2003 Jan;72(1):1-12. El Saghir NS et al. BRCA1 and BRCA2 mutations in ethnic Lebanese Arab women with high hereditary risk breast cancer. Oncologist. 2015 Apr;20(4):357-64. Lee E et al. Evaluation of unclassified variants in the breast cancer susceptibility genes BRCA1 and BRCA2 using five methods: results from a population-based study of young breast cancer patients. Breast Cancer Res. 2008;10(1):R19. -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 06, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 26, 2023	Observed in individuals with breast or prostate cancer (Edwards et al., 2003; Lee et al., 2008; El Saghir et al., 2015; Matta et al., 2022); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 5840G>A; This variant is associated with the following publications: (PMID: 12474142, 25777348, 18284688, 10923033, 29884841, 35264596, 31853058, 31911673, 32377563, 33471991, 36329109) -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 23, 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	Jan 06, 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). -

not specified Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 06, 2022	DNA sequence analysis of the BRCA2 gene demonstrated a sequence change, c.5612G>A, in exon 11 that results in an amino acid change, p.Ser1871Asn. This sequence change has been described in the gnomAD database with a frequency of 0.069% in the African/African American subpopulation (dbSNP rs80358782). The p.Ser1871Asn change affects a poorly conserved amino acid residue located in a domain of the BRCA2 protein that is known to be functional. The p.Ser1871Asn substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been previously described in individuals with BRCA2-related cancers, as well as in individuals with no history of cancer (PMID: 12474142, 25777348, 18284688, 33471991, FLOSSIES database https://whi.color.com/variant/13-32914104-G-A). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Ser1871Asn change remains unknown at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 29, 2024	Variant summary: BRCA2 c.5612G>A (p.Ser1871Asn) results in a conservative amino acid change located in the BRCA2 repeat; IPR002093 of the encoded protein sequence. Five 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 1610562 control chromosomes, predominantly at a frequency of 0.00057 within the African or African-American subpopulation in the gnomAD database (v4.0.0). This frequency is not significantly higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (3.2e-05 vs 0.00075), allowing no conclusion about variant significance. c.5612G>A has been reported in the literature in individuals affected with Breast And Ovarian Cancer (Edwards_2003, Lee_2008, El Saghir_2015, Dorling_2021) as well as in individuals without Breast And Ovarian Cancer (FLOSSIES database, Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variant(s) have been reported ( BRCA1 c.798_799delTT, p.Ser267LysfsX19), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 12474142, 18284688, 25777348, 33471991). ClinVar contains an entry for this variant (Variation ID: 51891). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary breast ovarian cancer syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	research	Genetics Program, Instituto Nacional de Cancer	Nov 01, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	- -

Hereditary cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	1.4
DANN	Benign	0.90
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.039	N
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.038	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.79	N;N
REVEL	Benign	0.061
Sift	Benign	0.55	T;T
Sift4G	Benign	1.0	T;T
Vest4		0.14
MVP		0.87
MPC		0.020
ClinPred		0.017	T
GERP RS		1.7
gMVP		0.081

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: rs80358782; hg19: chr13-32914104;