chr2-47783103-C-CCACTGGGGCCCGGGTTCCTCCGGCGGAGCGCGCCTCCCCCCAGATTTCCCGCCAGCAGGAGCCGCGCGGTAGATGCGGTGCTTTTAGGAGCTCCGTCCGACAGAACGGTTGGGCCTTGCCGGCTGTCGGTATGTCGCGACAGAGCACCCTGTACAGCTTCTTCCCCAAGTCTCCGGCGCTGAGTGATGCCAACAAGGCCTCGGCCAGGGCCTCACGCGAAGGCGGCCGTGCCGCCGCTGCCCCCGGGGCCTCTCCTTCCCCAGGCGGGGATGCGGCCTGGAGCGAGGCTGGGCCTGGGCCCAGGCCCTTGGCGCGCTCCGCGT

Position:

• chr2-47783103-C-CCACTGGGGCCCGGGTTCCTCCGGCGGAGCGCGCCTCCCCCCAGATTTCCCGCCAGCAGGAGCCGCGCGGTAGATGCGGTGCTTTTAGGAGCTCCGTCCGACAGAACGGTTGGGCCTTGCCGGCTGTCGGTATGTCGCGACAGAGCACCCTGTACAGCTTCTTCCCCAAGTCTCCGGCGCTGAGTGATGCCAACAAGGCCTCGGCCAGGGCCTCACGCGAAGGCGGCCGTGCCGCCGCTGCCCCCGGGGCCTCTCCTTCCCCAGGCGGGGATGCGGCCTGGAGCGAGGCTGGGCCTGGGCCCAGGCCCTTGGCGCGCTCCGCGT

Variant summary

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

The ENST00000234420.11(MSH6):​c.-127_196dupTGGGGCCCGGGTTCCTCCGGCGGAGCGCGCCTCCCCCCAGATTTCCCGCCAGCAGGAGCCGCGCGGTAGATGCGGTGCTTTTAGGAGCTCCGTCCGACAGAACGGTTGGGCCTTGCCGGCTGTCGGTATGTCGCGACAGAGCACCCTGTACAGCTTCTTCCCCAAGTCTCCGGCGCTGAGTGATGCCAACAAGGCCTCGGCCAGGGCCTCACGCGAAGGCGGCCGTGCCGCCGCTGCCCCCGGGGCCTCTCCTTCCCCAGGCGGGGATGCGGCCTGGAGCGAGGCTGGGCCTGGGCCCAGGCCCTTGGCGCGCTCCGCGTCAC​(p.Pro66fs) variant causes a frameshift, stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. P66P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MSH6 ENST00000234420.11 frameshift, stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.0580

Genes affected

MSH6 (HGNC:7329): (mutS homolog 6) This gene encodes a member of the DNA mismatch repair MutS family. In E. coli, the MutS protein helps in the recognition of mismatched nucleotides prior to their repair. A highly conserved region of approximately 150 aa, called the Walker-A adenine nucleotide binding motif, exists in MutS homologs. The encoded protein heterodimerizes with MSH2 to form a mismatch recognition complex that functions as a bidirectional molecular switch that exchanges ADP and ATP as DNA mismatches are bound and dissociated. Mutations in this gene may be associated with hereditary nonpolyposis colon cancer, colorectal cancer, and endometrial cancer. Transcripts variants encoding different isoforms have been described. [provided by RefSeq, Jul 2013]

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 2-47783103-C-CCACTGGGGCCCGGGTTCCTCCGGCGGAGCGCGCCTCCCCCCAGATTTCCCGCCAGCAGGAGCCGCGCGGTAGATGCGGTGCTTTTAGGAGCTCCGTCCGACAGAACGGTTGGGCCTTGCCGGCTGTCGGTATGTCGCGACAGAGCACCCTGTACAGCTTCTTCCCCAAGTCTCCGGCGCTGAGTGATGCCAACAAGGCCTCGGCCAGGGCCTCACGCGAAGGCGGCCGTGCCGCCGCTGCCCCCGGGGCCTCTCCTTCCCCAGGCGGGGATGCGGCCTGGAGCGAGGCTGGGCCTGGGCCCAGGCCCTTGGCGCGCTCCGCGT is Pathogenic according to our data. Variant chr2-47783103-C-CCACTGGGGCCCGGGTTCCTCCGGCGGAGCGCGCCTCCCCCCAGATTTCCCGCCAGCAGGAGCCGCGCGGTAGATGCGGTGCTTTTAGGAGCTCCGTCCGACAGAACGGTTGGGCCTTGCCGGCTGTCGGTATGTCGCGACAGAGCACCCTGTACAGCTTCTTCCCCAAGTCTCCGGCGCTGAGTGATGCCAACAAGGCCTCGGCCAGGGCCTCACGCGAAGGCGGCCGTGCCGCCGCTGCCCCCGGGGCCTCTCCTTCCCCAGGCGGGGATGCGGCCTGGAGCGAGGCTGGGCCTGGGCCCAGGCCCTTGGCGCGCTCCGCGT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1765255.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH6	NM_000179.3	c.-131_-130insCACTGGGGCCCGGGTTCCTCCGGCGGAGCGCGCCTCCCCCCAGATTTCCCGCCAGCAGGAGCCGCGCGGTAGATGCGGTGCTTTTAGGAGCTCCGTCCGACAGAACGGTTGGGCCTTGCCGGCTGTCGGTATGTCGCGACAGAGCACCCTGTACAGCTTCTTCCCCAAGTCTCCGGCGCTGAGTGATGCCAACAAGGCCTCGGCCAGGGCCTCACGCGAAGGCGGCCGTGCCGCCGCTGCCCCCGGGGCCTCTCCTTCCCCAGGCGGGGATGCGGCCTGGAGCGAGGCTGGGCCTGGGCCCAGGCCCTTGGCGCGCTCCGCGT		upstream_gene_variant		ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.-127_196dupTGGGGCCCGGGTTCCTCCGGCGGAGCGCGCCTCCCCCCAGATTTCCCGCCAGCAGGAGCCGCGCGGTAGATGCGGTGCTTTTAGGAGCTCCGTCCGACAGAACGGTTGGGCCTTGCCGGCTGTCGGTATGTCGCGACAGAGCACCCTGTACAGCTTCTTCCCCAAGTCTCCGGCGCTGAGTGATGCCAACAAGGCCTCGGCCAGGGCCTCACGCGAAGGCGGCCGTGCCGCCGCTGCCCCCGGGGCCTCTCCTTCCCCAGGCGGGGATGCGGCCTGGAGCGAGGCTGGGCCTGGGCCCAGGCCCTTGGCGCGCTCCGCGTCAC	p.Pro66fs	frameshift_variant, stop_gained	1/10	1	NM_000179.3	ENSP00000234420.5
MSH6	ENST00000234420.11	c.-131_-130insCACTGGGGCCCGGGTTCCTCCGGCGGAGCGCGCCTCCCCCCAGATTTCCCGCCAGCAGGAGCCGCGCGGTAGATGCGGTGCTTTTAGGAGCTCCGTCCGACAGAACGGTTGGGCCTTGCCGGCTGTCGGTATGTCGCGACAGAGCACCCTGTACAGCTTCTTCCCCAAGTCTCCGGCGCTGAGTGATGCCAACAAGGCCTCGGCCAGGGCCTCACGCGAAGGCGGCCGTGCCGCCGCTGCCCCCGGGGCCTCTCCTTCCCCAGGCGGGGATGCGGCCTGGAGCGAGGCTGGGCCTGGGCCCAGGCCCTTGGCGCGCTCCGCGT		upstream_gene_variant		1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 14

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 28, 2020

The c.-127_196dup323 gross duplication spans the 5'UTR and part of coding exon 1 in the MSH6 gene. The exact breakpoints of the duplication were not determined; however, additional RNA analysis identified this as a tandem duplication that is predicted to result in a translational frameshift with an alternate stop codon (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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: chr2-48010242;