Genetic Variant MSH3:p.Lys383ArgfsTer32 (chr5-80675095-CA-C) – ACMG Classification: Pathogenic (16 pts)

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_002439.5(MSH3):c.1148delA(p.Lys383ArgfsTer32) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000503 in 1,610,100 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

MSH3
NM_002439.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11O:1

Conservation

PhyloP100: 4.41

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 Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 5-80675095-CA-C is Pathogenic according to our data. Variant chr5-80675095-CA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-80675095-CA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH3	NM_002439.5 link	c.1148delA	p.Lys383ArgfsTer32	frameshift_variant	Exon 7 of 24	ENST00000265081.7	NP_002430.3	P20585

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MSH3	ENST00000265081.7 link	c.1148delA	p.Lys383ArgfsTer32	frameshift_variant	Exon 7 of 24	1	NM_002439.5	ENSP00000265081.6	P20585
MSH3	ENST00000658259.1 link	c.980delA	p.Lys327ArgfsTer32	frameshift_variant	Exon 7 of 24			ENSP00000499617.1	A0A590UJW0
MSH3	ENST00000667069.1 link	c.1148delA	p.Lys383ArgfsTer32	frameshift_variant	Exon 7 of 22			ENSP00000499502.1	A0A590UJN8
MSH3	ENST00000670357.1 link	n.1148delA		non_coding_transcript_exon_variant	Exon 7 of 25			ENSP00000499791.1	A0A590UKC9

Frequencies

GnomAD3 genomes

AF:

0.0000266

AC:

AN:

150644

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000591

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000528

AC:

AN:

1459456

Hom.:

Cov.:

AF XY:

0.0000647

AC XY:

AN XY:

726138

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000657

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

AF:

0.0000266

AC:

AN:

150644

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73444

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000591

Gnomad4 OTH

AF:

0.00

EpiCase

AF:

0.00

EpiControl

AF:

0.0000596

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 4

Pathogenic:3

Sep 01, 1996

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 29, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

Oct 21, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:3

Apr 13, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed with a second MSH3 variant in two siblings with multiple colorectal polyps, colorectal cancer, and other cancers (Adam et al., 2016); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34843512, 27476653, 28528517, 8782829) -

Aug 21, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MSH3 c.1148delA; p.Lys383Argfs*32 variant (rs587776701) has been previously published with a additional pathogenic variant on the opposite chromosome in an individual with autosomal recessive subtype4 of colorectal adenomatous polyposis (Adam 2016). The variant is reported as pathogenic in the ClinVar database (Variation ID: 8738) and is found in the general population with an overall allele frequency of 0.001079% (3/277,990 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Adam et al. Exome Sequencing Identifies Biallelic MSH3 Germline Mutations as a Recessive Subtype of Colorectal Adenomatous Polyposis. Am J Hum Genet. 2016 Aug 4;99(2):337-51. -

Jan 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Lys383Argfs*32) in the MSH3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH3 are known to be pathogenic (PMID: 27476653, 37402566). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with colorectal adenomatous polyposis (PMID: 27476653). ClinVar contains an entry for this variant (Variation ID: 8738). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (internal data). For these reasons, this variant has been classified as Pathogenic. -

Endometrial carcinoma

Pathogenic:3

Feb 12, 2021

Centogene AG - the Rare Disease Company

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 1996

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 02, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MSH3-related disorder

Pathogenic:1

Dec 12, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MSH3 c.1148delA variant is predicted to result in a frameshift and premature protein termination (p.Lys383Argfs*32). This variant has been reported to be pathogenic in a patient with autosomal recessive colorectal adenomatous polyposis (Adam et al. 2016. PubMed ID: 27476653). This variant is reported in 0.024% of alleles in individuals of European (Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/642843/). Frameshift variants in MSH3 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Sep 14, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1148delA pathogenic mutation, located in coding exon 7 of the MSH3 gene, results from a deletion of one nucleotide at nucleotide position 1148, causing a translational frameshift with a predicted alternate stop codon (p.K383Rfs*32). This mutation was reported along with another MSH3 pathogenic mutation in two sisters: one diagnosed with colorectal cancer, colon polyps and gastric cancer, and the other with colon and duodenal polyps, thyroid adenoma and intraductal papillomas. Both parents were unaffected (Adam R et al. Am. J. Hum. Genet., 2016 Aug;99:337-51). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Neoplasm

Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: -

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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.

5-80675095-CAAAA-CAAA

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