rs35032294

Positions:

• chr3-36993279-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000673673.2(MLH1):​c.-269C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00591 in 739,108 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0061 (12 hom.)
• Consequence: MLH1 ENST00000673673.2 5_prime_UTR
• Clinical Significance: Likely benign reviewed by expert panel B:5
• Conservation: PhyloP100: -1.46

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=-0.71).
• BP6: Variant 3-36993279-C-G is Benign according to our data. Variant chr3-36993279-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 89588.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-36993279-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00534 (813/152364) while in subpopulation AMR AF= 0.00875 (134/15312). AF 95% confidence interval is 0.00755. There are 3 homozygotes in gnomad4. There are 375 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000673673.2	c.-269C>G		5_prime_UTR_variant	1/18			ENSP00000500979

Frequencies

GnomAD3 genomes AF: 0.00535 AC: 814 AN: 152246 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00876

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00794

Gnomad OTH AF: 0.00525

GnomAD4 exome AF: 0.00606 AC: 3554 AN: 586744 Hom.: 12 Cov.: 7 AF XY: 0.00585 AC XY: 1784 AN XY: 304774

Gnomad4 AFR exome AF: 0.00176

Gnomad4 AMR exome AF: 0.00481

Gnomad4 ASJ exome AF: 0.00721

Gnomad4 EAS exome AF: 0.0000313

Gnomad4 SAS exome AF: 0.00308

Gnomad4 FIN exome AF: 0.00215

Gnomad4 NFE exome AF: 0.00762

Gnomad4 OTH exome AF: 0.00605

GnomAD4 genome AF: 0.00534 AC: 813 AN: 152364 Hom.: 3 Cov.: 33 AF XY: 0.00503 AC XY: 375 AN XY: 74498

Gnomad4 AFR AF: 0.00156

Gnomad4 AMR AF: 0.00875

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00331

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.00794

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00488 Hom.: 0

Bravo AF: 0.00584

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: reviewed by expert panel

Submissions by phenotype

Colorectal cancer, hereditary nonpolyposis, type 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Lynch syndrome Benign:1

Likely benign, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

No effect on transcription & MAF 0.01-1% -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2024

MLH1: BS2 -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 15, 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	-0.71
CADD	Benign	7.2
DANN	Benign	0.71

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs35032294; hg19: chr3-37034770;