rs397507341

Positions:

• chr13-32339205-G-A
• chr13-32339205-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_000059.4(BRCA2):​c.4850G>A​(p.Ser1617Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000366 in 1,613,338 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 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:6
• Conservation: PhyloP100: -0.386

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 Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15711543).
• BP6: Variant 13-32339205-G-A is Benign according to our data. Variant chr13-32339205-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 37928.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=4}. Variant chr13-32339205-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.4850G>A	p.Ser1617Asn	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.4850G>A	p.Ser1617Asn	missense_variant	11/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.4481G>A	p.Ser1494Asn	missense_variant	11/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.4850G>A		non_coding_transcript_exon_variant	10/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152112 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000120 AC: 3 AN: 249944 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135528

Gnomad AFR exome AF: 0.00

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: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000397 AC: 58 AN: 1461226 Hom.: 0 Cov.: 44 AF XY: 0.0000454 AC XY: 33 AN XY: 726982

Gnomad4 AFR exome AF: 0.0000299

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: 0.0000513

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152112 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74304

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

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: 0.0000434 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 13, 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	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 10, 2018	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Feb 14, 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). -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 03, 2021	Variant summary: BRCA2 c.4850G>A (p.Ser1617Asn) 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 1.4e-05 in 356946 control chromosomes (gnomAD and publications). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4850G>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Stegel_2011, Dorling_2021) but it was also reported in unaffected controls (Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A co-occurrence with a pathogenic variant has been reported (BRCA2 c.3599_3600delGT, p.Cys1200X; UMD), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and three ClinVar submitters (evaluation after 2014) cite it as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Uncertain significance, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 19, 2023	In the published literature, this variant has been reported in individuals with a personal or family history of breast and/or ovarian cancer (PMIDs: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BRCA2), 21120943 (2011), 21232165 (2011)). Additionally, the variant has been reported in healthy, unaffected individuals (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BRCA2)). The frequency of this variant in the general population, 0.000027 (3/113110 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. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2018	This variant is associated with the following publications: (PMID: 21232165, 21120943) -

Hereditary breast ovarian cancer syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 04, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Aug 04, 2021	- -

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

Likely benign, no assertion criteria provided

clinical testing

Sharing Clinical Reports Project (SCRP)

Oct 04, 2010

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	2.2
DANN	Benign	0.91
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.046	N
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.91	T
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.19
Sift	Benign	0.33	T;T
Sift4G	Benign	0.35	T;T
Vest4		0.29
MutPred		0.42		Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);
MVP		0.85
MPC		0.034
ClinPred		0.023	T
GERP RS		-1.1
gMVP		0.088

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: rs397507341; hg19: chr13-32913342;