rs1800734

Positions:

• chr3-36993455-G-A
• chr3-36993455-G-C
• chr3-36993455-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000413740.2(MLH1):​c.-93G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.244 in 1,283,016 control chromosomes in the GnomAD database, including 42,875 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4663 hom., cov: 33)
  • Exomes 𝑓: 0.25 (38212 hom.)
• Consequence: MLH1 ENST00000413740.2 5_prime_UTR
• Clinical Significance: Benign reviewed by expert panel U:1 B:11
• Conservation: PhyloP100: -0.737

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 3-36993455-G-A is Benign according to our data. Variant chr3-36993455-G-A is described in ClinVar as [Benign]. Clinvar id is 89600.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-36993455-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.538 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLH1	XM_047448155.1			upstream_gene_variant			XP_047304111.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000413740.2	c.-93G>A		5_prime_UTR_variant	1/15	1		ENSP00000416476
MLH1	ENST00000536378.5	c.-725G>A		5_prime_UTR_variant	1/18	2		ENSP00000444286
MLH1	ENST00000673673.2	c.-93G>A		5_prime_UTR_variant	1/18			ENSP00000500979

Frequencies

GnomAD3 genomes AF: 0.232 AC: 35278 AN: 152130 Hom.: 4667 Cov.: 33

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.274

Gnomad ASJ AF: 0.328

Gnomad EAS AF: 0.554

Gnomad SAS AF: 0.384

Gnomad FIN AF: 0.247

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.215

Gnomad OTH AF: 0.260

GnomAD4 exome AF: 0.246 AC: 278381 AN: 1130768 Hom.: 38212 Cov.: 16 AF XY: 0.251 AC XY: 144931 AN XY: 577786

Gnomad4 AFR exome AF: 0.168

Gnomad4 AMR exome AF: 0.329

Gnomad4 ASJ exome AF: 0.330

Gnomad4 EAS exome AF: 0.545

Gnomad4 SAS exome AF: 0.374

Gnomad4 FIN exome AF: 0.253

Gnomad4 NFE exome AF: 0.213

Gnomad4 OTH exome AF: 0.266

GnomAD4 genome AF: 0.232 AC: 35286 AN: 152248 Hom.: 4663 Cov.: 33 AF XY: 0.238 AC XY: 17732 AN XY: 74448

Gnomad4 AFR AF: 0.172

Gnomad4 AMR AF: 0.274

Gnomad4 ASJ AF: 0.328

Gnomad4 EAS AF: 0.554

Gnomad4 SAS AF: 0.383

Gnomad4 FIN AF: 0.247

Gnomad4 NFE AF: 0.215

Gnomad4 OTH AF: 0.262

Alfa AF: 0.235 Hom.: 8641

Bravo AF: 0.234

Asia WGS AF: 0.445 AC: 1546 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:11

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Colorectal cancer, hereditary nonpolyposis, type 2 Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Feb 15, 2007	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 27895767, 31530880, 24325908, 25804231, 25421847, 30093976, 22878509, 28195176, 26275295, 15382050, 22371642, 23226285, 24205329, 21206982, 21348638, 24689082, 17374836, 19956916, 18712731, 18405947, 18523027, 23374646, 20060799, 21565826, 23621208, 20860725) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Muir-Torré syndrome;C1333991:Colorectal cancer, hereditary nonpolyposis, type 2;C5399763:Mismatch repair cancer syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 02, 2022

- -

Lynch syndrome Benign:1

Benign, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

MAF >1% -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 18, 2014

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	3.6
DANN	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1800734; hg19: chr3-37034946; COSMIC: COSV99212309; COSMIC: COSV99212309;