rs1553665500

Variant names:

• chr3-37050490-A-C
• rs1553665500
• ENST00000450420.6:c.1563A>C

Your query was ambiguous. Multiple possible variants found:

• chr3-37050490-A-C
• chr3-37050490-A-G
• chr3-37050490-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The ENST00000450420.6(MLH1):​c.1563A>C​(p.Ter521Cysext*?) variant causes a stop lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. *521*) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MLH1 ENST00000450420.6 stop_lost
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 3.67

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in ENST00000450420.6 Downstream stopcodon found after 530 codons.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4	c.2108A>C	p.Glu703Ala	missense_variant	Exon 19 of 19	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.2108A>C	p.Glu703Ala	missense_variant	Exon 19 of 19	1	NM_000249.4	ENSP00000231790.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

May 14, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E703A variant (also known as c.2108A>C), located in coding exon 19 of the MLH1 gene, results from an A to C substitution at nucleotide position 2108. The glutamic acid at codon 703 is replaced by alanine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Mar 09, 2022

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

not provided Uncertain:1

Apr 15, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2 -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Sep 01, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid with alanine at codon 703 of the MLH1 protein (p.Glu703Ala). The glutamic acid residue is weakly conserved and there is a moderate physicochemical difference between glutamic acid and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	21
DANN	Benign	0.90
DEOGEN2	Uncertain	0.73	D;.;.;.;.;.
Eigen	Benign	-0.020
Eigen_PC	Benign	-0.051
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.82	T;T;.;.;.;T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.15	T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.7	L;.;.;.;.;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.9	N;.;N;N;N;N
REVEL	Uncertain	0.45
Sift	Benign	0.33	T;.;T;T;T;T
Sift4G	Benign	0.41	T;T;T;T;T;T
Polyphen		0.0020	B;.;.;.;.;.
Vest4		0.14
MutPred		0.17		Loss of disorder (P = 0.096);.;.;.;.;.;
MVP		0.95
MPC		0.071
ClinPred		0.18	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.092
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs1553665500; hg19: chr3-37091981; COSMIC: COSV51623426; COSMIC: COSV51623426;