ENST00000234420.11:c.-127_196dupTGGGGCCCGGGTTCCTCCGGCGGAGCGCGCCTCCCCCCAGATTTCCCGCCAGCAGGAGCCGCGCGGTAGATGCGGTGCTTTTAGGAGCTCCGTCCGACAGAACGGTTGGGCCTTGCCGGCTGTCGGTATGTCGCGACAGAGCACCCTGTACAGCTTCTTCCCCAAGTCTCCGGCGCTGAGTGATGCCAACAAGGCCTCGGCCAGGGCCTCACGCGAAGGCGGCCGTGCCGCCGCTGCCCCCGGGGCCTCTCCTTCCCCAGGCGGGGATGCGGCCTGGAGCGAGGCTGGGCCTGGGCCCAGGCCCTTGGCGCGCTCCGCGTCAC

Variant names:

• chr2-47783103-C-CCACTGGGGCCCGGGTTCCTCCGGCGGAGCGCGCCTCCCCCCAGATTTCCCGCCAGCAGGAGCCGCGCGGTAGATGCGGTGCTTTTAGGAGCTCCGTCCGACAGAACGGTTGGGCCTTGCCGGCTGTCGGTATGTCGCGACAGAGCACCCTGTACAGCTTCTTCCCCAAGTCTCCGGCGCTGAGTGATGCCAACAAGGCCTCGGCCAGGGCCTCACGCGAAGGCGGCCGTGCCGCCGCTGCCCCCGGGGCCTCTCCTTCCCCAGGCGGGGATGCGGCCTGGAGCGAGGCTGGGCCTGGGCCCAGGCCCTTGGCGCGCTCCGCGT
• ENST00000234420.11:c.-127_196dupTGGGGCCCGGGTTCCTCCGGCGGAGCGCGCCTCCCCCCAGATTTCCCGCCAGCAGGAGCCGCGCGGTAGATGCGGTGCTTTTAGGAGCTCCGTCCGACAGAACGGTTGGGCCTTGCCGGCTGTCGGTATGTCGCGACAGAGCACCCTGTACAGCTTCTTCCCCAAGTCTCCGGCGCTGAGTGATGCCAACAAGGCCTCGGCCAGGGCCTCACGCGAAGGCGGCCGTGCCGCCGCTGCCCCCGGGGCCTCTCCTTCCCCAGGCGGGGATGCGGCCTGGAGCGAGGCTGGGCCTGGGCCCAGGCCCTTGGCGCGCTCCGCGTCAC

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 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. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. 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
• Publications: 0 publications found

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]

MSH6 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
• Lynch syndrome 5

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Genomics England PanelApp
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• mismatch repair cancer syndrome 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P
• ovarian cancer

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• Muir-Torre syndrome

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• breast cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• 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 rank	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 rank	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.-127_196dupTGGGGCCCGGGTTCCTCCGGCGGAGCGCGCCTCCCCCCAGATTTCCCGCCAGCAGGAGCCGCGCGGTAGATGCGGTGCTTTTAGGAGCTCCGTCCGACAGAACGGTTGGGCCTTGCCGGCTGTCGGTATGTCGCGACAGAGCACCCTGTACAGCTTCTTCCCCAAGTCTCCGGCGCTGAGTGATGCCAACAAGGCCTCGGCCAGGGCCTCACGCGAAGGCGGCCGTGCCGCCGCTGCCCCCGGGGCCTCTCCTTCCCCAGGCGGGGATGCGGCCTGGAGCGAGGCTGGGCCTGGGCCCAGGCCCTTGGCGCGCTCCGCGTCAC	p.Pro66fs	frameshift_variant, stop_gained	Exon 1 of 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

Mar 28, 2020

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.058

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr2-48010242;