14-75013876-G-A

Variant names:

• chr14-75013876-G-A
• rs188135545
• NM_001040108.2:c.*3206C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS1

The NM_001040108.2(MLH3):​c.*3206C>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 0.00138 in 216,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: MLH3 NM_001040108.2 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.161
• Publications: 0 publications found

Genes affected

MLH3 (HGNC:7128): (mutL homolog 3) This gene is a member of the MutL-homolog (MLH) family of DNA mismatch repair (MMR) genes. MLH genes are implicated in maintaining genomic integrity during DNA replication and after meiotic recombination. The protein encoded by this gene functions as a heterodimer with other family members. Somatic mutations in this gene frequently occur in tumors exhibiting microsatellite instability, and germline mutations have been linked to hereditary nonpolyposis colorectal cancer type 7 (HNPCC7). Several alternatively spliced transcript variants have been identified, but the full-length nature of only two transcript variants has been determined. [provided by RefSeq, Jul 2008]

MLH3 Gene-Disease associations (from GenCC):

• colorectal cancer, hereditary nonpolyposis, type 7

  Inheritance: AD, AR Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, ClinGen, Laboratory for Molecular Medicine

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00183 (279/152240) while in subpopulation AFR AF = 0.00517 (215/41556). AF 95% confidence interval is 0.00461. There are 0 homozygotes in GnomAd4. There are 149 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH3	NM_001040108.2	c.*3206C>T		3_prime_UTR_variant	Exon 13 of 13	ENST00000355774.7	NP_001035197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH3	ENST00000355774.7	c.*3206C>T		3_prime_UTR_variant	Exon 13 of 13	5	NM_001040108.2	ENSP00000348020.2
MLH3	ENST00000380968.6	c.*3206C>T		3_prime_UTR_variant	Exon 12 of 12	1		ENSP00000370355.3

Frequencies

GnomAD3 genomes AF: 0.00181 AC: 275 AN: 152122 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00509

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00510

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000956

GnomAD4 exome AF: 0.000313 AC: 20 AN: 63816 Hom.: 0 Cov.: 0 AF XY: 0.000271 AC XY: 8 AN XY: 29514

African (AFR) AF: 0.00444 AC: 13 AN: 2930

American (AMR) AF: 0.00 AC: 0 AN: 1890

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4028

East Asian (EAS) AF: 0.00 AC: 0 AN: 9482

South Asian (SAS) AF: 0.00 AC: 0 AN: 544

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 54

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 412

European-Non Finnish (NFE) AF: 0.0000766 AC: 3 AN: 39140

Other (OTH) AF: 0.000750 AC: 4 AN: 5336

GnomAD4 genome AF: 0.00183 AC: 279 AN: 152240 Hom.: 0 Cov.: 33 AF XY: 0.00200 AC XY: 149 AN XY: 74444

African (AFR) AF: 0.00517 AC: 215 AN: 41556

American (AMR) AF: 0.000327 AC: 5 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00510 AC: 54 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68010

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000794 Hom.: 0

Bravo AF: 0.00164

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Colorectal cancer, hereditary nonpolyposis, type 7 Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.3
DANN	Benign	0.56
PhyloP100		0.16

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

Other links and lift over

dbSNP: rs188135545; hg19: chr14-75480579;