3-37047683-G-T

Variant names:

• chr3-37047683-G-T
• NM_000249.4:c.1896G>T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000249.4(MLH1):​c.1896G>T​(p.Glu632Asp) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E632E) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MLH1 NM_000249.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.64

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 3-37047683-G-T is Pathogenic according to our data. Variant chr3-37047683-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1782160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4	c.1896G>T	p.Glu632Asp	missense_variant, splice_region_variant	Exon 16 of 19	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.1896G>T	p.Glu632Asp	missense_variant, splice_region_variant	Exon 16 of 19	1	NM_000249.4	ENSP00000231790.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:1

Nov 06, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 8571956]. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Mar 15, 2021

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E632D variant (also known as c.1896G>T), located in coding exon 16 of the MLH1 gene, results from a G to T substitution at nucleotide position 1896. The amino acid change results in glutamic acid to aspartic acid at codon 632, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 16, which makes it likely to have some effect on normal mRNA splicing. A different variant at the same nucleotide position, c.1896G>A, has been classified as pathogenic based on identification in Lynch syndrome families and reportedly demonstrated aberrant splicing by RT-PCR analysis (Wijnen J et al. Am J Hum Genet. 1996 Feb;58(2):300-7; Wijnen J et al. Am J Hum Genet. 1997 Aug;61(2):329-35; Wagner A et al. J Med Genet. 2002 Nov;39(11):833-7; Ramsoekh D et al. Gut. 2008 Nov;57(11):1539-44; van Lier MG et al. J Pathol. 2012 Apr;226(5):764-74; De Lellis L et al. PLoS One. 2013 Nov 20;8(11):e81194). A different alteration (c.1896G>C) resulting in the same amino acid substitution (p.E632D) was identified in a Balkan patient with suspected Lynch syndrome (Goldberg Y et al. Clin. Genet., 2015 Jun;87:549-53) and in an individual diagnosed with MLH1-absent uterine cancer at age 46 (South SA et al. Obstet Gynecol, 2007 Aug;110:543-5). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. This amino acid position is not well conserved in available vertebrate species. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition, the in silico prediction for this variant as a missense substitution is inconclusive. 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
AlphaMissense	Benign	0.095
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.60	D;.;.;.;.;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;.;.;.;D
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.50	T;T;T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.5	L;.;.;.;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.62	N;N;N;N;N;N
REVEL	Uncertain	0.46
Sift	Benign	0.23	T;T;T;T;T;T
Sift4G	Benign	0.49	T;T;T;T;T;T
Polyphen		0.0	B;.;.;.;.;.
Vest4		0.53
MutPred		0.32		Loss of disorder (P = 0.2235);.;.;.;.;.;
MVP		0.90
MPC		0.061
ClinPred		0.70	D
GERP RS		4.6
Varity_R		0.30
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.73		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.73		Position offset: 0

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: chr3-37089174;