14-75014665-C-T

Variant names:

• chr14-75014665-C-T
• rs175049
• NM_001040108.2:c.*2417G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001040108.2(MLH3):​c.*2417G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.401 in 204,380 control chromosomes in the GnomAD database, including 17,304 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (12934 hom., cov: 33)
  • Exomes 𝑓: 0.39 (4370 hom.)
• Consequence: MLH3 NM_001040108.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.50
• Publications: 18 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 14-75014665-C-T is Benign according to our data. Variant chr14-75014665-C-T is described in ClinVar as [Benign]. Clinvar id is 314351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.454 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH3	NM_001040108.2	c.*2417G>A		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.*2417G>A		3_prime_UTR_variant	Exon 13 of 13	5	NM_001040108.2	ENSP00000348020.2
MLH3	ENST00000380968.6	c.*2417G>A		3_prime_UTR_variant	Exon 12 of 12	1		ENSP00000370355.3

Frequencies

GnomAD3 genomes AF: 0.404 AC: 61416 AN: 151864 Hom.: 12927 Cov.: 33

Gnomad AFR AF: 0.343

Gnomad AMI AF: 0.471

Gnomad AMR AF: 0.348

Gnomad ASJ AF: 0.473

Gnomad EAS AF: 0.153

Gnomad SAS AF: 0.462

Gnomad FIN AF: 0.444

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.458

Gnomad OTH AF: 0.420

GnomAD4 exome AF: 0.393 AC: 20598 AN: 52398 Hom.: 4370 Cov.: 0 AF XY: 0.397 AC XY: 9663 AN XY: 24364

African (AFR) AF: 0.334 AC: 786 AN: 2350

American (AMR) AF: 0.334 AC: 491 AN: 1468

Ashkenazi Jewish (ASJ) AF: 0.463 AC: 1549 AN: 3344

East Asian (EAS) AF: 0.161 AC: 1343 AN: 8336

South Asian (SAS) AF: 0.491 AC: 209 AN: 426

European-Finnish (FIN) AF: 0.325 AC: 13 AN: 40

Middle Eastern (MID) AF: 0.442 AC: 152 AN: 344

European-Non Finnish (NFE) AF: 0.448 AC: 14205 AN: 31698

Other (OTH) AF: 0.421 AC: 1850 AN: 4392

GnomAD4 genome AF: 0.404 AC: 61441 AN: 151982 Hom.: 12934 Cov.: 33 AF XY: 0.403 AC XY: 29939 AN XY: 74270

African (AFR) AF: 0.343 AC: 14213 AN: 41444

American (AMR) AF: 0.347 AC: 5302 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.473 AC: 1640 AN: 3470

East Asian (EAS) AF: 0.152 AC: 787 AN: 5172

South Asian (SAS) AF: 0.462 AC: 2224 AN: 4812

European-Finnish (FIN) AF: 0.444 AC: 4677 AN: 10530

Middle Eastern (MID) AF: 0.510 AC: 150 AN: 294

European-Non Finnish (NFE) AF: 0.458 AC: 31115 AN: 67964

Other (OTH) AF: 0.428 AC: 903 AN: 2112

Alfa AF: 0.433 Hom.: 18645

Bravo AF: 0.390

Asia WGS AF: 0.358 AC: 1243 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Colorectal cancer, hereditary nonpolyposis, type 7 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	7.3
DANN	Benign	0.67
PhyloP100		2.5
Mutation Taster		=100/0	polymorphism (auto)

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: rs175049; hg19: chr14-75481368;