rs1553648201

Positions:

• chr3-37020443-TCCAGGATGTACTTCAC-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_000249.4(MLH1):​c.1024_1038+1delATGTACTTCACCCAGG​(p.Met342_Gln346del) variant causes a splice donor, conservative inframe deletion, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MLH1 NM_000249.4 splice_donor, conservative_inframe_deletion, splice_region, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.29

Genes affected

MLH1 (HGNC:7127): (mutL homolog 1) The protein encoded by this gene can heterodimerize with mismatch repair endonuclease PMS2 to form MutL alpha, part of the DNA mismatch repair system. When MutL alpha is bound by MutS beta and some accessory proteins, the PMS2 subunit of MutL alpha introduces a single-strand break near DNA mismatches, providing an entry point for exonuclease degradation. The encoded protein is also involved in DNA damage signaling and can heterodimerize with DNA mismatch repair protein MLH3 to form MutL gamma, which is involved in meiosis. This gene was identified as a locus frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). [provided by RefSeq, Aug 2017]

MLH1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.067371204 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.2, offset of 0 (no position change), new splice context is: cagGTcagg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-37020443-TCCAGGATGTACTTCAC-T is Pathogenic according to our data. Variant chr3-37020443-TCCAGGATGTACTTCAC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 495757.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
MLH1	NM_000249.4	c.1024_1038+1delATGTACTTCACCCAGG	p.Met342_Gln346del	splice_donor_variant, conservative_inframe_deletion, splice_region_variant, intron_variant	11/19	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.1024_1038+1delATGTACTTCACCCAGG	p.Met342_Gln346del	splice_donor_variant, conservative_inframe_deletion, splice_region_variant, intron_variant	11/19	1	NM_000249.4	ENSP00000231790.3

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/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 16, 2021	This variant deletes 16 nucleotides in exon 11 of the MLH1 gene, predicted to create a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 30, 2024	The c.1024_1038+1del16 variant results from a deletion of 16 nucleotides between positions 1024 and 1038+1 and involves the canonical splice donor site after coding exon 11 of the MLH1 gene. This variant has been identified in a proband(s) who met Amsterdam I/II criteria for Lynch syndrome; however, immunohistochemistry and microsatellite instability results from these tumors were not always consistent with MLH1-related disease (Pino MS et al. J Mol Diagn. 2009 May;11(3):238-47; Cruz-Correa M et al. Fam. Cancer. 2015 Sep;14(3):415-25; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This canonical splice donor site is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Jul 19, 2023

This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. -

Lynch syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 21, 2016

Variant summary: The MLH1 c.1024_1038+1delATGTACTTCACCCAGG variant involves the deletion of 16 nucleotides around the exon/intron 11 border. Mutation taster predicts a damaging outcome for this substitution while 5/5 splice site tools predicts the variant to create a splice site at nucleotide 1023. The aberrant splicing product is predicted to result in an in-frame deletion p.Met342_Gln346del deletion (Alamut). This variant is absent in 120030 control chromosomes. It was reported in multiple LS patients (Pino_2009, Cruz-Correa_2015) and at least one family, it was shown to co-segregate with the disease in two affected family members, strongly supporting for causality. Taken together, this variant is classified as pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 06, 2023

This sequence change creates a premature translational stop signal (Splice site) in the MLH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 19324997, 25782445; Invitae). This variant is also known as c.1024del16 and c.1024_1038+1del. ClinVar contains an entry for this variant (Variation ID: 495757). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553648201; hg19: chr3-37061934;