rs587778964

Variant names:

• chr3-37048604-A-C
• rs587778964
• NM_000249.4:c.1984A>C

Your query was ambiguous. Multiple possible variants found:

• chr3-37048604-A-C
• chr3-37048604-A-G
• chr3-37048604-A-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000249.4(MLH1):​c.1984A>C​(p.Thr662Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T662A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MLH1 NM_000249.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 8.88

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 16 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 15 uncertain 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 chr3-37048605-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3633429.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.877
• PP5: Variant 3-37048604-A-C is Pathogenic according to our data. Variant chr3-37048604-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 89968.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37048604-A-C is described in Lovd as [Likely_pathogenic]. Variant chr3-37048604-A-C is described in Lovd as [Pathogenic]. Variant chr3-37048604-A-C is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4	c.1984A>C	p.Thr662Pro	missense_variant	Exon 17 of 19	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.1984A>C	p.Thr662Pro	missense_variant	Exon 17 of 19	1	NM_000249.4	ENSP00000231790.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:2

Jul 25, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 27363726]. -

Oct 24, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary nonpolyposis colon cancer Pathogenic:1

Dec 30, 2024

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MLH1 c.1984A>C (p.Thr662Pro) results in a non-conservative amino acid change located in the DNA mismatch repair protein Mlh1, C-terminal (IPR032189) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249912 control chromosomes. c.1984A>C has been reported in the literature in multiple individuals affected with Lynch Syndrome/Hereditary Nonpolyposis Colorectal Cancer Lynch Syndrome (example, Hardt_2011, Pagenstecher_2006, Kruger_2001, Takahashi_2007). These data indicate that the variant is very likely to be associated with disease. Multiple publications report experimental evidence evaluating an impact on protein function (example, Takahashi_2007, Kosinski_2010, Hinrichsen_2013, Borras_2012). The most pronounced variant effect results in a moderate (approx 60%) reduction in mismatch repair (MMR) activity (Takahashi_2007) while another study reporting a proficient MMR activity characterized the variant as being stability deficient (Hinrichsen_2013). The following publications have been ascertained in the context of this evaluation (PMID: 22736432, 18383312, 21404117, 23403630, 20533529, 11754112, 17192056, 36454741, 16341550, 17510385, 24362816, 23760103). ClinVar contains an entry for this variant (Variation ID: 89968). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Lynch syndrome Pathogenic:1

Jun 21, 2019

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

Abrogated function (2 independent assays with reduced expression) & 6 MSI-H tumours -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 662 of the MLH1 protein (p.Thr662Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Lynch syndrome (PMID: 11726306, 11754112, 16341550, 19621678, 21404117, 34897210). ClinVar contains an entry for this variant (Variation ID: 89968). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt MLH1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MLH1 function (PMID: 17510385, 20533529, 23403630, 31332305). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Sep 22, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T662P variant (also known as c.1984A>C), located in coding exon 17 of the MLH1 gene, results from an A to C substitution at nucleotide position 1984. The threonine at codon 662 is replaced by proline, an amino acid with highly similar properties. This variant was reported in four individuals from four different families who met Bethesda guidelines. Furthermore, tumor analysis revealed MSI-H in all four individuals and IHC revealed three individuals had loss of MLH1 as well as PMS2 and one individual had loss of MLH1 (Hardt K et al., Fam. Cancer 2011 Jun; 10(2):273-84). This variant has also been reported in families meeting Amsterdam criteria (Müller-Koch Y et al. Eur. J. Med. Res., 2001 Nov;6:473-82; Krüger S et al. Hum. Mutat., 2002 Jan;19:82). Additional studies combining family history, segregation with disease, functional analyses, and/or in silico predictions have also demonstrated that this alteration is likely pathogenic (Thompson BA et al., Nat. Genet. 2014 Feb; 46(2):107-15). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D;.;.;.;.;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;.;.;.;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Benign	1.4	L;.;.;.;.;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.8	D;D;D;D;D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.019	D;D;D;D;D;D
Sift4G	Uncertain	0.050	T;D;D;D;D;D
Polyphen		0.070	B;.;.;.;.;.
Vest4		0.87
MutPred		0.78		Loss of sheet (P = 0.0011);.;.;.;.;.;
MVP		0.99
MPC		0.16
ClinPred		0.94	D
GERP RS		5.5
Varity_R		0.90
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs587778964; hg19: chr3-37090095;