rs587778886

Positions:

• chr3-36993441-C-G
• chr3-36993441-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS1

The ENST00000413740(MLH1):​c.-107C>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 0.0000307 in 1,008,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: MLH1 ENST00000413740 5_prime_UTR
• Clinical Significance: Likely benign reviewed by expert panel U:2 B:4
• Conservation: PhyloP100: -0.325

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP6: Variant 3-36993441-C-G is Benign according to our data. Variant chr3-36993441-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 89587.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-36993441-C-G is described in Lovd as [Likely_benign]. Variant chr3-36993441-C-G is described in Lovd as [Likely_pathogenic].
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000307 (31/1008238) while in subpopulation EAS AF= 0.000796 (30/37672). AF 95% confidence interval is 0.000573. There are 0 homozygotes in gnomad4_exome. There are 16 alleles in male gnomad4_exome subpopulation. Median coverage is 14. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
		n.36993441C>G		intergenic_region
MLH1	XM_047448155.1	c.-646C>G		upstream_gene_variant			XP_047304111.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000413740	c.-107C>G		5_prime_UTR_variant	1/15	1		ENSP00000416476.2
MLH1	ENST00000673673	c.-107C>G		5_prime_UTR_variant	1/18			ENSP00000500979.2
MLH1	ENST00000536378	c.-739C>G		5_prime_UTR_variant	1/18	2		ENSP00000444286.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000307 AC: 31 AN: 1008238 Hom.: 0 Cov.: 14 AF XY: 0.0000307 AC XY: 16 AN XY: 521466

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000796

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000220

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2 Benign:4

Revision: reviewed by expert panel

Submissions by phenotype

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

Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Oct 09, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Sema4, Sema4

Sep 16, 2021

- -

Lynch syndrome Benign:1

Likely benign, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

Multifactorial likelihood analysis posterior probability 0.001-0.049 -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	5.0
DANN	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.27		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs587778886; hg19: chr3-37034932;