rs587776701

Variant names:

• chr5-80675095-CAAAA-C
• NM_002439.5:c.1145_1148delAAAA

Your query was ambiguous. Multiple possible variants found:

• chr5-80675095-CAAAA-C
• chr5-80675095-CAAAA-CAAA
• chr5-80675095-CAAAA-CAAAAA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_002439.5(MSH3):​c.1145_1148delAAAA​(p.Lys382ArgfsTer32) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH3 NM_002439.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.41

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-80675095-CAAAA-C is Pathogenic according to our data. Variant chr5-80675095-CAAAA-C is described in ClinVar as [Pathogenic]. Clinvar id is 2810274.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH3	NM_002439.5	c.1145_1148delAAAA	p.Lys382ArgfsTer32	frameshift_variant	Exon 7 of 24	ENST00000265081.7	NP_002430.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH3	ENST00000265081.7	c.1145_1148delAAAA	p.Lys382ArgfsTer32	frameshift_variant	Exon 7 of 24	1	NM_002439.5	ENSP00000265081.6
MSH3	ENST00000658259.1	c.977_980delAAAA	p.Lys326ArgfsTer32	frameshift_variant	Exon 7 of 24			ENSP00000499617.1
MSH3	ENST00000667069.1	c.1145_1148delAAAA	p.Lys382ArgfsTer32	frameshift_variant	Exon 7 of 22			ENSP00000499502.1
MSH3	ENST00000670357.1	n.1145_1148delAAAA		non_coding_transcript_exon_variant	Exon 7 of 25			ENSP00000499791.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Oct 27, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys382Argfs*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). This variant has not been reported in the literature in individuals affected with MSH3-related conditions. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-79970914;