5-80675095-CAAAA-CAAAAA

Variant names:

• chr5-80675095-C-CA
• rs587776701
• NM_002439.5:c.1148dupA

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_002439.5(MSH3):​c.1148dupA​(p.Asn385GlnfsTer19) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. K383K) has been classified as Likely benign. 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
• Publications: 38 publications found

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 Gene-Disease associations (from GenCC):

• familial adenomatous polyposis 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• MSH3-related attenuated familial adenomatous polyposis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Lynch syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 643621.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002439.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH3	NM_002439.5	MANE Select	c.1148dupA	p.Asn385GlnfsTer19	frameshift	Exon 7 of 24	NP_002430.3	P20585

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH3	ENST00000265081.7	TSL:1 MANE Select	c.1148dupA	p.Asn385GlnfsTer19	frameshift	Exon 7 of 24	ENSP00000265081.6	P20585
	MSH3	ENST00000658259.1		c.980dupA	p.Asn329GlnfsTer19	frameshift	Exon 7 of 24	ENSP00000499617.1	A0A590UJW0
	MSH3	ENST00000667069.1		c.1148dupA	p.Asn385GlnfsTer19	frameshift	Exon 7 of 22	ENSP00000499502.1	A0A590UJN8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 248208 AF XY: 0.00000745

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33314

American (AMR) AF: 0.00 AC: 0 AN: 44522

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26056

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39572

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86026

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5740

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1110550

Other (OTH) AF: 0.0000166 AC: 1 AN: 60252

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000506523), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000504 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
1	-	-	Endometrial carcinoma (1)
1	-	-	Endometrial carcinoma;C4310719:Familial adenomatous polyposis 4 (1)
1	-	-	Familial adenomatous polyposis 4 (1)
1	-	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.4
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587776701; hg19: chr5-79970914; COSMIC: COSV54145912;