rs80358880

Positions:

• chr13-32340798-C-A
• chr13-32340798-C-G
• chr13-32340798-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000059.4(BRCA2):​c.6443C>A​(p.Ser2148Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 1,592,576 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S2148A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:8
• Conservation: PhyloP100: -0.529

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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25916934).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.6443C>A	p.Ser2148Tyr	missense_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.6443C>A	p.Ser2148Tyr	missense_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000259 AC: 6 AN: 231302 Hom.: 0 AF XY: 0.0000320 AC XY: 4 AN XY: 125084

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000340

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: 0.0000463

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000125 AC: 18 AN: 1440370 Hom.: 0 Cov.: 44 AF XY: 0.0000126 AC XY: 9 AN XY: 715684

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000512

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: 0.0000136

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152206 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74356

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000302

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Feb 20, 2004	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 18, 2015	- -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Apr 27, 2012	- -

not specified Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 23, 2020	DNA sequence analysis of the BRCA2 gene demonstrated a sequence change, c.6443C>A, in exon 11 that results in an amino acid change, p.Ser2148Tyr. This sequence change has been previously described in patient cohorts with breast and ovarian cancer but no additional information was provided to assess its significance (PMIDs: 29088781, 16284991 and 16905680). It has been described in the gnomAD database with a low population frequency of 0.0027% (dbSNP rs80358880). The p.Ser2148Tyr change affects a moderately conserved amino acid residue located in a domain of the BRCA2 protein that is known to be functional. The p.Ser2148Tyr substitution appears to be possibly benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Ser2148Tyr change remains unknown at this time. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 09, 2022	Variant summary: BRCA2 c.6443C>A (p.Ser2148Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.6e-05 in 231562 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6443C>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likelye benign n=6, VUS n=3). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 04, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 22, 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:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 09, 2020	This variant is associated with the following publications: (PMID: 10923033, 16284991, 16905680, 17262179, 29088781, 30995915, 31131967) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 04, 2023	The frequency of this variant in the general population, 0.000049 (6/123370 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast and/or ovarian cancer (PMID: 16284991 (2005), 16905680 (2007), 17262179 (2007), 29088781 (2017), 34204722 (2021)). A large multifactorial analysis study has classified the variant as a variant of uncertain significance (PMID: 31131967 (2019)). A large multifactorial analysis study has classified the variant as having a low clinical significance (PMID: 31131967 (2019)). 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. -

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.Ser2148Tyr variant was identified in 2 of 930 proband chromosomes (frequency 0.002) from individuals or families with breast or ovarian cancer (Pal 2005, Simard 2007); however, control chromosomes were not evaluated in these studies. The variant was also identified in dbSNP (ID: rs80358880) “With non-pathogenic allele”, UMD (1X as an unclassified variant), and the BIC database (7X with unknown clinical importance). The variant was listed in the NHLBI Exome Sequencing Project in 1 of 8600 European American alleles (frequency: 0.0001), increasing the likelihood that this may represent a low frequency benign variant in certain populations. This residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. 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 unknown significance. -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 17, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	0.0023	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	11
DANN	Benign	0.66
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.034	N
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-0.81	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.1	N;N
REVEL	Uncertain	0.53
Sift	Benign	0.052	T;T
Sift4G	Benign	0.66	T;T
Vest4		0.32
MVP		0.86
MPC		0.083
ClinPred		0.051	T
GERP RS		-0.98
gMVP		0.28

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: rs80358880; hg19: chr13-32914935; COSMIC: COSV99061668;