NM_001040108.2:c.*1877T>C

Variant names:

• chr14-75015205-A-G
• rs108622
• NM_001040108.2:c.*1877T>C

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.*1877T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.394 in 176,520 control chromosomes in the GnomAD database, including 14,451 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (12485 hom., cov: 32)
  • Exomes 𝑓: 0.38 (1966 hom.)
• Consequence: MLH3 NM_001040108.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.21
• 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=-0.55).
• BP6: Variant 14-75015205-A-G is Benign according to our data. Variant chr14-75015205-A-G is described in ClinVar as [Benign]. Clinvar id is 314356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.453 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH3	NM_001040108.2	c.*1877T>C		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.*1877T>C		3_prime_UTR_variant	Exon 13 of 13	5	NM_001040108.2	ENSP00000348020.2
MLH3	ENST00000380968.6	c.*1877T>C		3_prime_UTR_variant	Exon 12 of 12	1		ENSP00000370355.3

Frequencies

GnomAD3 genomes AF: 0.395 AC: 60088 AN: 151976 Hom.: 12478 Cov.: 32

Gnomad AFR AF: 0.313

Gnomad AMI AF: 0.470

Gnomad AMR AF: 0.343

Gnomad ASJ AF: 0.472

Gnomad EAS AF: 0.153

Gnomad SAS AF: 0.461

Gnomad FIN AF: 0.444

Gnomad MID AF: 0.509

Gnomad NFE AF: 0.458

Gnomad OTH AF: 0.413

GnomAD4 exome AF: 0.383 AC: 9352 AN: 24426 Hom.: 1966 Cov.: 0 AF XY: 0.382 AC XY: 4253 AN XY: 11134

African (AFR) AF: 0.324 AC: 248 AN: 766

American (AMR) AF: 0.361 AC: 184 AN: 510

Ashkenazi Jewish (ASJ) AF: 0.459 AC: 722 AN: 1572

East Asian (EAS) AF: 0.162 AC: 859 AN: 5288

South Asian (SAS) AF: 0.505 AC: 104 AN: 206

European-Finnish (FIN) AF: 0.375 AC: 6 AN: 16

Middle Eastern (MID) AF: 0.480 AC: 72 AN: 150

European-Non Finnish (NFE) AF: 0.453 AC: 6325 AN: 13954

Other (OTH) AF: 0.424 AC: 832 AN: 1964

GnomAD4 genome AF: 0.395 AC: 60114 AN: 152094 Hom.: 12485 Cov.: 32 AF XY: 0.395 AC XY: 29330 AN XY: 74340

African (AFR) AF: 0.313 AC: 12978 AN: 41490

American (AMR) AF: 0.342 AC: 5230 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.472 AC: 1634 AN: 3464

East Asian (EAS) AF: 0.153 AC: 793 AN: 5182

South Asian (SAS) AF: 0.461 AC: 2227 AN: 4826

European-Finnish (FIN) AF: 0.444 AC: 4690 AN: 10558

Middle Eastern (MID) AF: 0.507 AC: 149 AN: 294

European-Non Finnish (NFE) AF: 0.457 AC: 31096 AN: 67970

Other (OTH) AF: 0.421 AC: 889 AN: 2114

Alfa AF: 0.421 Hom.: 5417

Bravo AF: 0.380

Asia WGS AF: 0.355 AC: 1232 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 12, 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	-0.55
CADD	Benign	13
DANN	Benign	0.61
PhyloP100		1.2
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: rs108622; hg19: chr14-75481908;