rs1805355

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002439.5(MSH3):c.693G>A(p.Pro231=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0846 in 1,613,768 control chromosomes in the GnomAD database, including 10,567 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P231P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.12 ( 1656 hom., cov: 33)

Exomes 𝑓: 0.081 ( 8911 hom. )

Consequence

MSH3
NM_002439.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.01

Variant links:

Genes affected

MSH3 (HGNC:7326): (mutS homolog 3) The protein encoded by this gene forms a heterodimer with MSH2 to form MutS beta, part of the post-replicative DNA mismatch repair system. MutS beta initiates mismatch repair by binding to a mismatch and then forming a complex with MutL alpha heterodimer. This gene contains a polymorphic 9 bp tandem repeat sequence in the first exon. The repeat is present 6 times in the reference genome sequence and 3-7 repeats have been reported. Defects in this gene are a cause of susceptibility to endometrial cancer. [provided by RefSeq, Mar 2011]

MSH3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 5-80670210-G-A is Benign according to our data. Variant chr5-80670210-G-A is described in ClinVar as [Benign]. Clinvar id is 810935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-80670210-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.01 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.322 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH3	NM_002439.5 linkuse as main transcript	c.693G>A	p.Pro231=	synonymous_variant	4/24	ENST00000265081.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
MSH3	ENST00000265081.7 linkuse as main transcript	c.693G>A	p.Pro231=	synonymous_variant	4/24	1	NM_002439.5	P2
MSH3	ENST00000658259.1 linkuse as main transcript	c.525G>A	p.Pro175=	synonymous_variant	4/24			A2
MSH3	ENST00000667069.1 linkuse as main transcript	c.693G>A	p.Pro231=	synonymous_variant	4/22
MSH3	ENST00000670357.1 linkuse as main transcript	c.693G>A	p.Pro231=	synonymous_variant, NMD_transcript_variant	4/25

Frequencies

GnomAD3 genomes

AF:

0.124

AC:

18876

AN:

151932

Hom.:

1652

Cov.:

show subpopulations

Gnomad AFR

AF:

0.192

Gnomad AMI

AF:

0.0835

Gnomad AMR

AF:

0.211

Gnomad ASJ

AF:

0.130

Gnomad EAS

AF:

0.336

Gnomad SAS

AF:

0.0876

Gnomad FIN

AF:

0.0654

Gnomad MID

AF:

0.0791

Gnomad NFE

AF:

0.0602

Gnomad OTH

AF:

0.110

GnomAD3 exomes

AF:

0.135

AC:

33835

AN:

251416

Hom.:

4092

AF XY:

0.121

AC XY:

16458

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.190

Gnomad AMR exome

AF:

0.348

Gnomad ASJ exome

AF:

0.137

Gnomad EAS exome

AF:

0.326

Gnomad SAS exome

AF:

0.0802

Gnomad FIN exome

AF:

0.0703

Gnomad NFE exome

AF:

0.0590

Gnomad OTH exome

AF:

0.107

GnomAD4 exome

AF:

0.0805

AC:

117705

AN:

1461718

Hom.:

8911

Cov.:

AF XY:

0.0794

AC XY:

57750

AN XY:

727172

show subpopulations

Gnomad4 AFR exome

AF:

0.189

Gnomad4 AMR exome

AF:

0.331

Gnomad4 ASJ exome

AF:

0.137

Gnomad4 EAS exome

AF:

0.364

Gnomad4 SAS exome

AF:

0.0820

Gnomad4 FIN exome

AF:

0.0712

Gnomad4 NFE exome

AF:

0.0555

Gnomad4 OTH exome

AF:

0.0948

GnomAD4 genome

AF:

0.124

AC:

18900

AN:

152050

Hom.:

1656

Cov.:

AF XY:

0.127

AC XY:

9465

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.192

Gnomad4 AMR

AF:

0.211

Gnomad4 ASJ

AF:

0.130

Gnomad4 EAS

AF:

0.335

Gnomad4 SAS

AF:

0.0877

Gnomad4 FIN

AF:

0.0654

Gnomad4 NFE

AF:

0.0602

Gnomad4 OTH

AF:

0.110

Alfa

AF:

0.0764

Hom.:

1692

Bravo

AF:

0.145

Asia WGS

AF:

0.179

AC:

620

AN:

3478

EpiCase

AF:

0.0577

EpiControl

AF:

0.0584

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2018	This variant is associated with the following publications: (PMID: 21128252, 27884173) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Hereditary cancer-predisposing syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 10, 2018	This alteration is classified as 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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Apr 28, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

6.5

DANN

Benign

0.43

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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