chr5-80675095-C-CA

Position:

• chr5-80675095-C-CA

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_002439.5(MSH3):​c.1148dupA​(p.Asn385fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000754 in 1,459,408 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: MSH3 NM_002439.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• 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 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-C-CA is Pathogenic according to our data. Variant chr5-80675095-C-CA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 643621.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH3	NM_002439.5	c.1148dupA	p.Asn385fs	frameshift_variant	7/24	ENST00000265081.7	NP_002430.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH3	ENST00000265081.7	c.1148dupA	p.Asn385fs	frameshift_variant	7/24	1	NM_002439.5	ENSP00000265081.6
MSH3	ENST00000658259.1	c.980dupA	p.Asn329fs	frameshift_variant	7/24			ENSP00000499617.1
MSH3	ENST00000667069.1	c.1148dupA	p.Asn385fs	frameshift_variant	7/22			ENSP00000499502.1
MSH3	ENST00000670357.1	n.1148dupA		non_coding_transcript_exon_variant	7/25			ENSP00000499791.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000754 AC: 11 AN: 1459408 Hom.: 0 Cov.: 31 AF XY: 0.00000964 AC XY: 7 AN XY: 726118

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	MSH3: PVS1, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 24, 2023	This sequence change creates a premature translational stop signal (p.Asn385Glnfs*19) 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 variant has not been reported in the literature in individuals affected with MSH3-related conditions. ClinVar contains an entry for this variant (Variation ID: 643621). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 09, 2024	The MSH3 c.1148dup (p.Asn385Glnfs*19) variant alters the translational reading frame of the MSH3 mRNA and is predicted to cause the premature termination of MSH3 protein synthesis. This variant has not been reported in individuals with MSH3-related conditions in the published literature. The frequency of this variant in the general population, 0.000004 (1/248208 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, this variant is classified as likely pathogenic. -

Familial adenomatous polyposis 4 Pathogenic:1

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. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 17, 2023

The c.1148dupA pathogenic mutation, located in coding exon 7 of the MSH3 gene, results from a duplication of A at nucleotide position 1148, causing a translational frameshift with a predicted alternate stop codon (p.N385Qfs*19). 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. -

Endometrial carcinoma;C4310719:Familial adenomatous polyposis 4 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 26, 2024

- -

Endometrial carcinoma Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 17, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs587776701; hg19: chr5-79970914;