rs765655952

Positions:

• chr13-32370973-A-G
• chr13-32370973-A-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_000059.4(BRCA2):​c.8505A>G​(p.Ser2835Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,461,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: BRCA2 NM_000059.4 synonymous
• Clinical Significance: Likely benign reviewed by expert panel B:9
• Conservation: PhyloP100: -0.480

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 13-32370973-A-G is Benign according to our data. Variant chr13-32370973-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 385641.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32370973-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.48 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.8505A>G	p.Ser2835Ser	synonymous_variant	20/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.8505A>G	p.Ser2835Ser	synonymous_variant	20/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.8136A>G	p.Ser2712Ser	synonymous_variant	20/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*563A>G		non_coding_transcript_exon_variant	19/26	2		ENSP00000506251.1
BRCA2	ENST00000614259.2	n.*563A>G		3_prime_UTR_variant	19/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251190 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135732

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1461808 Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11 AN XY: 727202

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:9

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 19, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 21, 2019	- -

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

Likely benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Jun 29, 2017	Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/). -
Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 20, 2023	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 31, 2016	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	Jul 25, 2017	- -

BRCA2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 09, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Malignant tumor of breast Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The p.Ser2835Ser variant has not been previously identified in the literature. This variant is not expected to have clinical significance because it does not alter an amino acid residue, and is not located near a splice junction. Another variant, c.8503T>C, p.Ser2835Pro, impacting the same position has been reported (Caux-Moncoutier 2009). In the UMD database, the c.8503T>C, p.Ser2835Pro variant has been identified in 2 (out of 13) individuals with breast or ovarian cancers, where a second pathogenic BRCA mutations was also detected, increasing the likelihood that an alteration to this residue does not have clinical significance. Furthermore, in one report, a cell line derived from a faconia anemia patient was identified with a nonsense mutation at this residue that reverted to Glutamic acid (p.Ser2835Glu), and corrected the cellular phenotype, increasing the likelihood an alteration at this residue does not have functional significance (Ikeda 2003). In addition, the patient referred to our laboratory was indicated as being of "Asian" racial background and we have sequenced a limited number of individuals from this population such that the full spectrum of benign variation may not yet be defined for this population and increasing the likelihood the p.Ser2835Ser variant may be benign. In summary, based on the above information, we cannot determine the clinical significance of this variant with certainty at this time, although we would lean towards a more benign role for this variant. In summary, this variant is classified as Predicted Benign. -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 18, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.43
DANN	Benign	0.59

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: rs765655952; hg19: chr13-32945110;