rs775390721

Variant summary

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

The ENST00000233146.7(MSH2):ā€‹c.2621A>Gā€‹(p.Tyr874Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,461,780 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. Y874H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)
Exomes š‘“: 0.000013 ( 1 hom. )

Consequence

MSH2
ENST00000233146.7 missense

Scores

1
18

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: 0.253
Variant links:
Genes affected
MSH2 (HGNC:7325): (mutS homolog 2) This locus is frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). When cloned, it was discovered to be a human homolog of the E. coli mismatch repair gene mutS, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in HNPCC. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

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=0.106799334).
BP6
Variant 2-47480858-A-G is Benign according to our data. Variant chr2-47480858-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 525750.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=1, Uncertain_significance=4}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MSH2NM_000251.3 linkuse as main transcriptc.2621A>G p.Tyr874Cys missense_variant 15/16 ENST00000233146.7 NP_000242.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MSH2ENST00000233146.7 linkuse as main transcriptc.2621A>G p.Tyr874Cys missense_variant 15/161 NM_000251.3 ENSP00000233146 P1P43246-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.0000199
AC:
5
AN:
251406
Hom.:
0
AF XY:
0.0000368
AC XY:
5
AN XY:
135872
show subpopulations
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:
0.000163
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000130
AC:
19
AN:
1461780
Hom.:
1
Cov.:
32
AF XY:
0.0000206
AC XY:
15
AN XY:
727188
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000186
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31
Bravo
AF:
0.00000756
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoMar 23, 2023The frequency of this variant in the general population, 0.00016 (5/30610 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in a control individual in a large scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH2)). 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. -
Uncertain significance, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicJul 09, 2024PM2 -
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 27, 2022The p.Y874C variant (also known as c.2621A>G), located in coding exon 15 of the MSH2 gene, results from an A to G substitution at nucleotide position 2621. The tyrosine at codon 874 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was seen in 1/732 breast cancer patients, 0/189 colorectal cancer patients and 0/490 cancer-free elderly controls in a Turkish population (Akcay IM et al. Int J Cancer, 2021 Jan;148:285-295). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Likely benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthSep 09, 2015- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpSep 24, 2018Variant summary: MSH2 c.2621A>G (p.Tyr874Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 246210 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2621A>G in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
MSH2-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesDec 03, 2023The MSH2 c.2621A>G variant is predicted to result in the amino acid substitution p.Tyr874Cys. This variant has been reported in an individual with breast cancer (Table S6, Akcay et al. 2021. PubMed ID: 32658311). This variant is reported in 0.016% of alleles in individuals of South Asian descent in gnomAD. This variant has conflicting interpretations of benign, likely benign. and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/525750/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Hereditary nonpolyposis colorectal neoplasms Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 12, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.092
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Benign
-0.17
CADD
Benign
14
DANN
Benign
0.93
DEOGEN2
Benign
0.29
T;.;.;.
Eigen
Benign
-0.66
Eigen_PC
Benign
-0.47
FATHMM_MKL
Benign
0.46
N
LIST_S2
Benign
0.81
T;T;T;T
M_CAP
Benign
0.032
D
MetaRNN
Benign
0.11
T;T;T;T
MetaSVM
Benign
-0.54
T
MutationAssessor
Benign
0.29
N;.;.;.
MutationTaster
Benign
0.95
N;N;N
PrimateAI
Benign
0.31
T
PROVEAN
Benign
-1.3
N;N;.;N
REVEL
Uncertain
0.48
Sift
Benign
0.18
T;T;.;T
Sift4G
Benign
0.18
T;T;.;T
Polyphen
0.0
B;.;.;B
Vest4
0.25
MutPred
0.37
Gain of catalytic residue at L875 (P = 0.0112);.;Gain of catalytic residue at L875 (P = 0.0112);Gain of catalytic residue at L875 (P = 0.0112);
MVP
0.90
MPC
0.0061
ClinPred
0.039
T
GERP RS
2.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.11
gMVP
0.32

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.

Other links and lift over

dbSNP: rs775390721; hg19: chr2-47707997; API