3-37050685-C-T

Position:

• chr3-37050685-C-T

Variant summary

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

The NM_000249.4(MLH1):​c.*32C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,543,852 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00082 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (9 hom.)
• Consequence: MLH1 NM_000249.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 0.0580

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=-0.84).
• BP6: Variant 3-37050685-C-T is Benign according to our data. Variant chr3-37050685-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 135561.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37050685-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000817 (119/145662) while in subpopulation SAS AF= 0.00502 (24/4784). AF 95% confidence interval is 0.00346. There are 1 homozygotes in gnomad4. There are 68 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLH1	NM_000249.4	c.*32C>T		3_prime_UTR_variant	19/19	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.*32C>T		3_prime_UTR_variant	19/19	1	NM_000249.4	ENSP00000231790.3

Frequencies

GnomAD3 genomes AF: 0.000824 AC: 120 AN: 145564 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000205

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000748

Gnomad ASJ AF: 0.00711

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00501

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0201

Gnomad NFE AF: 0.000689

Gnomad OTH AF: 0.00100

GnomAD3 exomes AF: 0.00158 AC: 395 AN: 250380 Hom.: 2 AF XY: 0.00180 AC XY: 244 AN XY: 135424

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00625

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00565

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000916

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.00110 AC: 1537 AN: 1398190 Hom.: 9 Cov.: 27 AF XY: 0.00128 AC XY: 893 AN XY: 696698

Gnomad4 AFR exome AF: 0.000128

Gnomad4 AMR exome AF: 0.00117

Gnomad4 ASJ exome AF: 0.00580

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00616

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000664

Gnomad4 OTH exome AF: 0.00147

GnomAD4 genome AF: 0.000817 AC: 119 AN: 145662 Hom.: 1 Cov.: 32 AF XY: 0.000955 AC XY: 68 AN XY: 71238

Gnomad4 AFR AF: 0.000179

Gnomad4 AMR AF: 0.000747

Gnomad4 ASJ AF: 0.00711

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00502

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000689

Gnomad4 OTH AF: 0.000993

Alfa AF: 0.000750 Hom.: 0

Bravo AF: 0.000820

ClinVar

Significance: Likely benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Colorectal cancer, hereditary nonpolyposis, type 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.3
DANN	Benign	0.65

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: rs200903126; hg19: chr3-37092176;