rs1805355

Variant names:

• chr5-80670210-G-A
• rs1805355
• NM_002439.5:c.693G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-80670210-G-A
• chr5-80670210-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002439.5(MSH3):​c.693G>A​(p.Pro231Pro) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.01
• Publications: 33 publications found

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 Gene-Disease associations (from GenCC):

• familial adenomatous polyposis 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• MSH3-related attenuated familial adenomatous polyposis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Lynch syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 810935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
MSH3	NM_002439.5	c.693G>A	p.Pro231Pro	synonymous_variant	Exon 4 of 24	ENST00000265081.7	NP_002430.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH3	ENST00000265081.7	c.693G>A	p.Pro231Pro	synonymous_variant	Exon 4 of 24	1	NM_002439.5	ENSP00000265081.6
MSH3	ENST00000658259.1	c.525G>A	p.Pro175Pro	synonymous_variant	Exon 4 of 24			ENSP00000499617.1
MSH3	ENST00000667069.1	c.693G>A	p.Pro231Pro	synonymous_variant	Exon 4 of 22			ENSP00000499502.1
MSH3	ENST00000670357.1	n.693G>A		non_coding_transcript_exon_variant	Exon 4 of 25			ENSP00000499791.1

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18876 AN: 151932 Hom.: 1652 Cov.: 33

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

GnomAD2 exomes AF: 0.135 AC: 33835 AN: 251416 AF XY: 0.121

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 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.: 32 AF XY: 0.0794 AC XY: 57750 AN XY: 727172

African (AFR) AF: 0.189 AC: 6310 AN: 33464

American (AMR) AF: 0.331 AC: 14819 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 3589 AN: 26130

East Asian (EAS) AF: 0.364 AC: 14425 AN: 39674

South Asian (SAS) AF: 0.0820 AC: 7076 AN: 86256

European-Finnish (FIN) AF: 0.0712 AC: 3806 AN: 53418

Middle Eastern (MID) AF: 0.0460 AC: 265 AN: 5766

European-Non Finnish (NFE) AF: 0.0555 AC: 61689 AN: 1111902

Other (OTH) AF: 0.0948 AC: 5726 AN: 60384

GnomAD4 genome AF: 0.124 AC: 18900 AN: 152050 Hom.: 1656 Cov.: 33 AF XY: 0.127 AC XY: 9465 AN XY: 74336

African (AFR) AF: 0.192 AC: 7965 AN: 41448

American (AMR) AF: 0.211 AC: 3217 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 451 AN: 3468

East Asian (EAS) AF: 0.335 AC: 1730 AN: 5162

South Asian (SAS) AF: 0.0877 AC: 423 AN: 4826

European-Finnish (FIN) AF: 0.0654 AC: 692 AN: 10576

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0602 AC: 4093 AN: 67996

Other (OTH) AF: 0.110 AC: 232 AN: 2102

Alfa AF: 0.0845 Hom.: 4113

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Nov 05, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 21128252, 27884173) -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:3

Sep 10, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 23, 2024

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The synonymous variant NM_002439.5(MSH3):c.693G>A (p.Pro231=) has been reported to ClinVar as Benign with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 810935 as of 2024-12-05). The p.Pro231= variant is not predicted to disrupt an existing splice site. The p.Pro231= variant results in a substitution of a base that is not predicted conserved by GERP++ and PhyloP. For these reasons, this variant has been classified as Benign. -

Apr 28, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	6.5
DANN	Benign	0.43
PhyloP100		-1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1805355; hg19: chr5-79966029; COSMIC: COSV54159336;