NM_002439.5(MSH3):c.1148del (p.Lys383fs) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jan 10, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000822053.20

Allele description [Variation Report for NM_002439.5(MSH3):c.1148del (p.Lys383fs)]

NM_002439.5(MSH3):c.1148del (p.Lys383fs)

Gene:

MSH3:mutS homolog 3 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

5q14.1

Genomic location:

Preferred name:

NM_002439.5(MSH3):c.1148del (p.Lys383fs)

HGVS:

NC_000005.10:g.80675103del
NC_000005.9:g.79970915del
NG_016607.2:g.25629del
NM_002439.5:c.1148delMANE SELECT
NP_002430.3:p.Lys383Argfs
NP_002430.3:p.Lys383fs
NC_000005.9:g.79970915del
NC_000005.9:g.79970922del
NC_000005.9:g.79970922delA
NG_016607.1:g.25629del
NM_002439.3:c.1148delA
NM_002439.4:c.1148del
NM_002439.4:c.1148delA

Note:

NCBI staff reviewed the sequence information reported in PubMed 8782829 Fig. 1 to determine the location of this allele on the current reference sequence.

Protein change:

K383fs

Links:

OMIM: 600887.0001; dbSNP: rs587776701

NCBI 1000 Genomes Browser:

rs587776701

Molecular consequence:

NM_002439.5:c.1148del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000962837	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 10, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 37402566, 27476653, 28492532
SCV001471704	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Pathogenic (Aug 21, 2020)	germline	clinical testing	Citation Link,
SCV002818087	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Apr 13, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000962837

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 10, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV001471704

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)

Pathogenic
(Aug 21, 2020)

germline

clinical testing

Citation Link,

SCV002818087

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Apr 13, 2023)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

MSH3: a confirmed predisposing gene for adenomatous polyposis.

Villy MC, Masliah-Planchon J, Schnitzler A, Delhomelle H, Buecher B, Filser M, Merchadou K, Golmard L, Melaabi S, Vacher S, Blanluet M, Suybeng V, Corsini C, Dhooge M, Hamzaoui N, Farelly S, Ait Omar A, Benamouzig R, Caumette V, Bahuau M, Cucherousset J, Allory Y, et al.

J Med Genet. 2023 Nov 27;60(12):1198-1205. doi: 10.1136/jmg-2023-109341.

PubMed [citation]

PMID:: 37402566

Exome Sequencing Identifies Biallelic MSH3 Germline Mutations as a Recessive Subtype of Colorectal Adenomatous Polyposis.

Adam R, Spier I, Zhao B, Kloth M, Marquez J, Hinrichsen I, Kirfel J, Tafazzoli A, Horpaopan S, Uhlhaas S, Stienen D, Friedrichs N, Altmüller J, Laner A, Holzapfel S, Peters S, Kayser K, Thiele H, Holinski-Feder E, Marra G, Kristiansen G, Nöthen MM, et al.

Am J Hum Genet. 2016 Aug 4;99(2):337-51. doi: 10.1016/j.ajhg.2016.06.015. Epub 2016 Jul 28.

PubMed [citation]

PMID:: 27476653
PMCID:: PMC4974087

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000962837.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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 (Invitae). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001471704.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneDx, SCV002818087.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 7, 2024

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