rs80358439

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

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).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000097 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:8

Conservation

PhyloP100: -0.137

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=7, Uncertain_significance=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.1550A>G	p.Asn517Ser	missense_variant	Exon 10 of 27	ENST00000380152.8	NP_000050.3	P51587

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
BRCA2	ENST00000380152.8 link	c.1550A>G	p.Asn517Ser	missense_variant	Exon 10 of 27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 link	c.1181A>G	p.Asn394Ser	missense_variant	Exon 10 of 27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 link	n.1550A>G		non_coding_transcript_exon_variant	Exon 9 of 26	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

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:

AN:

233352

Hom.:

AF XY:

0.0000238

AC XY:

AN XY:

126180

show subpopulations

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:

AN:

1443866

Hom.:

Cov.:

AF XY:

0.0000139

AC XY:

AN XY:

717510

show subpopulations

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:

AN:

152338

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74502

show subpopulations

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.:

Bravo

AF:

0.0000302

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:2Benign:2

Feb 20, 2004

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 01, 2023

Department of Medical and Surgical Sciences, University of Bologna

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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) -

Jan 08, 2013

Sharing Clinical Reports Project (SCRP)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 21, 2014

Counsyl

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:3

Mar 23, 2023

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -

May 22, 2017

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 23, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Aug 28, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided

Uncertain:2

Feb 20, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Predicted to likely not be pathogenic based on tumor pathology, clinical histories, family studies, and co-occurrence with deleterious mutations (PMID: 21990134); In silico analysis indicates that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 1778A>G; This variant is associated with the following publications: (PMID: 27930734, 31131967, 32438681, 30287823, 25556971, 18824701, 26780556, 22476429, 26689913, 32377563, 34326862, 36243179, 35641219, 21990134, 37335020, 31907386, 34290354, 30254663) -

Feb 21, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.1550A>G (p.Asn517Ser) variant has been reported in the published literature as being likely benign based on multifactorial analyses (PMIDs: 21990134 (2012) and 18824701 (2008)). It has also been reported in affected individuals with breast and/or ovarian cancer (PMIDs: 35641219 (2022), 34290354 (2021), and 32438681 (2020)), as well as in large breast cancer association studies in both breast cancer cases as well as in reportedly healthy individuals (PMIDs: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)), 30287823 (2018), 25556971 (2015), and 22476429 (2012)). A functional study reported this variant had no effect on splicing (PMID: 26780556 (2016)). The frequency of this variant in the general population, 0.000015 (4/264752 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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:1Benign:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 22, 2023

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Hereditary cancer

Benign:1

Feb 27, 2025

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity. -

Hereditary breast ovarian cancer syndrome

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.33

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

M_CAP

Benign

0.027

MetaRNN

Benign

0.045

T;T

MetaSVM

Benign

-0.92

PrimateAI

Benign

0.19

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over