rs80358765

Positions:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_000059.4(BRCA2):c.5414A>G(p.Asn1805Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000632 in 1,613,980 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).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:13B:9

Conservation

PhyloP100: -0.126

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 -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.19550696).

BP6

Variant 13-32339769-A-G is Benign according to our data. Variant chr13-32339769-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 51858.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Benign=3, Uncertain_significance=10}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.5414A>G	p.Asn1805Ser	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 linkuse as main transcript	c.5414A>G	p.Asn1805Ser	missense_variant	11/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000557

AC:

AN:

251178

Hom.:

AF XY:

0.0000516

AC XY:

AN XY:

135788

show subpopulations

Gnomad AFR exome

AF:

0.000370

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000568

AC:

AN:

1461664

Hom.:

Cov.:

AF XY:

0.0000523

AC XY:

AN XY:

727126

show subpopulations

Gnomad4 AFR exome

AF:

0.000926

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.000513

GnomAD4 genome

AF:

0.000125

AC:

AN:

152316

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.000385

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000896

Hom.:

Bravo

AF:

0.0000982

ExAC

AF:

0.0000412

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:13Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:6

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 04, 2021	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 14, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Feb 20, 2004	- -

not provided

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 20, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 5642A>G; Observed in individuals with breast or ovarian cancer (PMID: 18559594, 26287763, 29854292, 34503154, 37335020, 33471991); This variant is associated with the following publications: (PMID: 29854292, 9971877, 18559594, 11929857, 27527004, 19139070, 10923033, 26287763, 31256854, 33868589, 33643918, 35464868, 34503154, 33471991, 10453741, 37335020) -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 14, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 20, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 03, 2022	- -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 14, 2015	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Mar 18, 2022	- -
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). -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 28, 2022	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. -

Hereditary breast ovarian cancer syndrome

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Apr 19, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Feb 14, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	- -

Fanconi anemia complementation group D1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The BRCA2 p.Asn1805Ser variant was identified in 3 of 1982 proband chromosomes (frequency: 0.002) from individuals or families with hereditary breast and ovarian cancer syndrome and was present in 1 of 190 control chromosomes (frequency: 0.005) from healthy individuals (Pal 2015, Soegaard 2008, Wagner 1999, Encinas 2018). The variant was also identified in dbSNP (ID: rs80358765) as "with uncertain significance allele", ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx and six other submitters; and as likely benign by Invitae and Color), and the LOVD 3.0 database. The variant was not identified in UMD-LSDB database. It was also identified in control databases in 18 of 276966 chromosomes at a frequency of 0.00007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 9 of 24018 chromosomes (freq: 0.0004), Other in 1 of 6456 chromosomes (freq: 0.0002), European in 2 of 126516 chromosomes (freq: 0.00002), and South Asian in 6 of 30774 chromosomes (freq: 0.0002), while the variant was not observed in the Latino, Ashkenazi Jewish, East Asian or Finnish populations. The p.Asn1805Ser residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and three out of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, Human Splicing Finder) predict a greater than 10% difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

May 09, 2024

Variant summary: BRCA2 c.5414A>G (p.Asn1805Ser) 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 6.4e-05 in 1614022 control chromosomes, predominantly at a frequency of 0.00063 within the African or African-American subpopulation in the gnomAD database (v4.0.0). This frequency is close to the estimated maximum for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (0.00075). The variant was also reported from the southern part of Africa with even higher allele frequencies, e.g. 0.014 (3/208 alleles; in the GenomeAsia 100K database) and 0.027 (Oosthuizen_2021), supporting a benign role for the variant. c.5414A>G has been reported in the literature in individuals affected with breast- and/or ovarian cancer (e.g. Soegaard_2008, Pal_2015, Encinas_2018), but was also found in controls (Wagner_1999). . 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: 10453741, 11929857, 18559594, 26287763, 29854292, 33643918, 33868589). ClinVar contains an entry for this variant (Variation ID: 51858). Based on the evidence outlined above, the variant was classified as likely benign. -

Inherited breast cancer and ovarian cancer

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service

May 02, 2024

BS1_Strong,BP1,BP4 -

Familial cancer of breast

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Feb 09, 2024

ACMG codes applied following ENIGMA VCEP rules: BP1_STR -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.50

CADD

Benign

1.3

DANN

Benign

0.80

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.20

M_CAP

Benign

0.052

MetaRNN

Benign

0.20

T;T

MetaSVM

Benign

-0.89

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.27

PROVEAN

Uncertain

-3.3

D;D

REVEL

Benign

0.13

Sift

Benign

0.14

T;T

Sift4G

Benign

0.31

T;T

Vest4

0.22

MVP

0.85

MPC

0.023

ClinPred

0.093

GERP RS

5.7

gMVP

0.097

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