14-75047266-C-T

Variant names:

• chr14-75047266-C-T
• rs28756991
• NM_001040108.2:c.2390G>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.2390G>A​(p.Arg797His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00351 in 1,614,070 control chromosomes in the GnomAD database, including 174 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R797C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.019 (93 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (81 hom.)
• Consequence: MLH3 NM_001040108.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.0430
• Publications: 13 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 (MetaRNN=0.0017323792).
• BP6: Variant 14-75047266-C-T is Benign according to our data. Variant chr14-75047266-C-T is described in ClinVar as Benign. ClinVar VariationId is 314383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0645 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040108.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH3	NM_001040108.2	MANE Select	c.2390G>A	p.Arg797His	missense	Exon 2 of 13	NP_001035197.1
	MLH3	NM_014381.3		c.2390G>A	p.Arg797His	missense	Exon 2 of 12	NP_055196.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH3	ENST00000355774.7	TSL:5 MANE Select	c.2390G>A	p.Arg797His	missense	Exon 2 of 13	ENSP00000348020.2
	MLH3	ENST00000380968.6	TSL:1	c.2390G>A	p.Arg797His	missense	Exon 2 of 12	ENSP00000370355.3
	MLH3	ENST00000930871.1		c.2390G>A	p.Arg797His	missense	Exon 2 of 13	ENSP00000600930.1

Frequencies

GnomAD3 genomes AF: 0.0189 AC: 2869 AN: 152126 Hom.: 92 Cov.: 33

Gnomad AFR AF: 0.0664

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00570

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.00488 AC: 1227 AN: 251392 AF XY: 0.00344

Gnomad AFR exome AF: 0.0666

Gnomad AMR exome AF: 0.00327

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00190 AC: 2778 AN: 1461826 Hom.: 81 Cov.: 35 AF XY: 0.00161 AC XY: 1172 AN XY: 727214

African (AFR) AF: 0.0659 AC: 2205 AN: 33476

American (AMR) AF: 0.00378 AC: 169 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5768

European-Non Finnish (NFE) AF: 0.0000576 AC: 64 AN: 1111984

Other (OTH) AF: 0.00502 AC: 303 AN: 60392

GnomAD4 genome AF: 0.0189 AC: 2885 AN: 152244 Hom.: 93 Cov.: 33 AF XY: 0.0182 AC XY: 1355 AN XY: 74450

African (AFR) AF: 0.0666 AC: 2766 AN: 41530

American (AMR) AF: 0.00556 AC: 85 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68022

Other (OTH) AF: 0.0119 AC: 25 AN: 2108

Alfa AF: 0.00725 Hom.: 70

Bravo AF: 0.0218

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0620 AC: 273

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00609 AC: 740

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Colorectal cancer, hereditary nonpolyposis, type 7 (3)
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Endometrial carcinoma (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.10
DANN	Benign	0.076
DEOGEN2	Benign	0.076	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0099	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.35	N
PhyloP100		-0.043
PrimateAI	Benign	0.25	T
PROVEAN	Benign	1.5	N
REVEL	Benign	0.083
Sift	Benign	0.93	T
Sift4G	Benign	0.82	T
Polyphen		0.0	B
Vest4		0.046
MVP		0.49
MPC		0.12
ClinPred		0.0022	T
GERP RS		-0.69
PromoterAI		-0.0054	Neutral
Varity_R		0.021
gMVP		0.18
Mutation Taster		=298/2	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: rs28756991; hg19: chr14-75513969; COSMIC: COSV104996920;