rs80358439

chr13-32333028-A-Gchr13-32333028-A-T

Variant summary

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

The NM_000059.4(BRCA2):c.1550A>G(p.Asn517Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000107 in 1,596,204 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N517D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000097 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:7
• Conservation: PhyloP100: -0.137

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=0.044884235).
• BP6: Variant 13-32333028-A-G is Benign according to our data. Variant chr13-32333028-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 37745.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=5}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.1550A>G	p.Asn517Ser	missense_variant	10/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.1550A>G	p.Asn517Ser	missense_variant	10/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000129 AC: 3 AN: 233352 Hom.: 0 AF XY: 0.0000238 AC XY: 3 AN XY: 126180

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000337

Gnomad ASJ exome AF: 0.000112

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000920

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000970 AC: 14 AN: 1443866 Hom.: 0 Cov.: 35 AF XY: 0.0000139 AC XY: 10 AN XY: 717510

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000252

Gnomad4 ASJ exome AF: 0.0000793

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000489

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000452

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152338 Hom.: 0 Cov.: 32 AF XY: 0.0000268 AC XY: 2 AN XY: 74502

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000110 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:3 Benign:2

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)	Jan 08, 2013	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Medical and Surgical Sciences, University of Bologna	Sep 01, 2023	BP1(Strong)+BP5(Supporting) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042) -
Likely benign, criteria provided, single submitter	literature only	Counsyl	Nov 21, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:3

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Nov 23, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 22, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 28, 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). -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 13, 2018	This variant is denoted BRCA2 c.1550A>G at the cDNA level, p.Asn517Ser (N517S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). Using alternate nomenclature, this variant would be defined as BRCA2 1778A>G. This variant was observed in at least two families with a history of breast and/or ovarian cancer (Lu 2012, Quiles 2016), as well as in an individual with glioma (Lu 2015). BRCA2 Asn517Ser was predicted by Lindor et al. (2012) to be likely not pathogenic (IARC Class 2) based on tumor pathology, clinical histories, family studies, and co-occurrence with deleterious mutations. BRCA2 Asn517Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Asn517Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 06, 2023	The frequency of this variant in the general population, 0.000015 (4/264752 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been predicted to be likely benign based on multifactorial analyses (PMID: 21990134 (2012), 18824701 (2008)). It has also been reported in an individual with breast and/or ovarian cancer (PMID: 32438681 (2020)) and in large breast cancer association studies in both affected and unaffected individuals (PMID: 33471991 (2021), 30287823 (2018), 25556971 (2015), 22476429 (2012)). A functional study reported this variant had no effect on splicing (PMID: 26780556 (2016)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 22, 2023	Variant summary: BRCA2 c.1550A>G (p.Asn517Ser) results in a conservative amino acid change in 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 1.3e-05 in 233352 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1550A>G has been reported in the literature in individuals with a personal or family history of breast and/or ovarian cancer (Trujillano_2014, Spearman_2008, Quiles_2016, Lu_2012, Zuntini_2018, Kim_2020, Abdel-Razeq_2021, Vargas_2022), however it was also found in unaffected control individuals (Momozawa_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. The variant was reported to have no effect on splicing based on analysis of mRNA extracted from patient derived lymphocytes (Quiles_2016), however deleterious effects at the protein level cannot be ruled out. The variant was predicted to be neutral based on a multifactorial probability model that performed systematic assessment of tumor pathology, clinical histories, family studies and co-occurrence with deleterious mutations (Lindor_2012). In addition, using a model based on tumor pathology and genetics including receptor status, tumor grade, loss of heterozygosity, and co-occurrence with deleterious mutations the variant was also suggested to be neutral (Spearman_2008). The following publications have been ascertained in the context of this evaluation (PMID: 34290354, 27930734, 31907386, 21990134, 22476429, 30287823, 26780556, 18824701, 25556971, 35641219, 30254663). Multiple submitters have reported clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments: five submitters classified the variant as uncertain significance, and five submitters classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	0.0070
Dann	Benign	0.21
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0040	N
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.045	T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.19	T
PROVEAN	Benign	0.11	N;N
REVEL	Benign	0.16
Sift	Benign	0.68	T;T
Sift4G	Benign	0.77	T;T
Vest4		0.072
MutPred		0.16		Gain of glycosylation at N517 (P = 0.0144);Gain of glycosylation at N517 (P = 0.0144);
MVP		0.72
MPC		0.019
ClinPred		0.019	T
GERP RS		-2.9
gMVP		0.052

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: rs80358439; hg19: chr13-32907165; COSMIC: COSV66451879;