Variant chr5-80675095-CA-C details in Genebe, Genetics Data Aggregator

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.Lys383fs) 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:10O: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/exons	MANE	Protein	UniProt
MSH3	NM_002439.5 linkuse as main transcript	c.1148delA	p.Lys383fs	frameshift_variant	7/24	ENST00000265081.7	NP_002430.3	P20585

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MSH3	ENST00000265081.7 linkuse as main transcript	c.1148delA	p.Lys383fs	frameshift_variant	7/24	1	NM_002439.5	ENSP00000265081.6	P20585
MSH3	ENST00000658259.1 linkuse as main transcript	c.980delA	p.Lys327fs	frameshift_variant	7/24			ENSP00000499617.1	A0A590UJW0
MSH3	ENST00000667069.1 linkuse as main transcript	c.1148delA	p.Lys383fs	frameshift_variant	7/22			ENSP00000499502.1	A0A590UJN8
MSH3	ENST00000670357.1 linkuse as main transcript	n.1148delA		non_coding_transcript_exon_variant	7/25			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:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 21, 2020	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 13, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 10, 2024	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. -

Endometrial carcinoma

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Feb 12, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 1996	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 02, 2024	- -

Familial adenomatous polyposis 4

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 1996	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Aug 29, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

MSH3-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 12, 2023

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2022

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

-, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

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.

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