rs121912965

Positions:

• chr3-36993651-TG-AC

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PS1_Moderate PM1 PM2 PM5 PP3 PP5_Very_Strong

The NM_000249.4(MLH1):​c.104_105delTGinsAC​(p.Met35Asn) variant causes a missense 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 Pathogenic (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M35K) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MLH1 NM_000249.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 7.62

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 17 ACMG points.

• PS1: Transcript NM_000249.4 (MLH1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a helix (size 13) in uniprot entity MLH1_HUMAN there are 19 pathogenic changes around while only 8 benign (70%) in NM_000249.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-36993650-ATG-AAA is described in Lovd as [Pathogenic].
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 3-36993651-TG-AC is Pathogenic according to our data. Variant chr3-36993651-TG-AC is described in ClinVar as [Pathogenic]. Clinvar id is 17105.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLH1	NM_000249.4	c.104_105delTGinsAC	p.Met35Asn	missense_variant		ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.104_105delTGinsAC	p.Met35Asn	missense_variant		1	NM_000249.4	ENSP00000231790.3

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2007

- -

Lynch syndrome Pathogenic:1

Pathogenic, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

Multifactorial likelihood analysis posterior probability >0.99 -

Mismatch repair cancer syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2007

- -

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: rs121912965; hg19: chr3-37035142;