rs372089146

chr14-75047300-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001040108.2(MLH3):c.2356G>A(p.Val786Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000669 in 1,614,078 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V786A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000065 (0 hom.)
• Consequence: MLH3 NM_001040108.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 0.0880

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010609686).
• BP6: Variant 14-75047300-C-T is Benign according to our data. Variant chr14-75047300-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 478025.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000853 (13/152322) while in subpopulation EAS AF= 0.00154 (8/5190). AF 95% confidence interval is 0.000767. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLH3	NM_001040108.2	c.2356G>A	p.Val786Ile	missense_variant	2/13	ENST00000355774.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLH3	ENST00000355774.7	c.2356G>A	p.Val786Ile	missense_variant	2/13	5	NM_001040108.2	P1
MLH3	ENST00000380968.6	c.2356G>A	p.Val786Ile	missense_variant	2/12	1
MLH3	ENST00000556257.5	c.2356G>A	p.Val786Ile	missense_variant	2/7	5

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000135 AC: 34 AN: 251414 Hom.: 0 AF XY: 0.000155 AC XY: 21 AN XY: 135890

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00158

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.0000650 AC: 95 AN: 1461756 Hom.: 0 Cov.: 35 AF XY: 0.0000688 AC XY: 50 AN XY: 727194

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00144

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.000563

GnomAD4 genome AF: 0.0000853 AC: 13 AN: 152322 Hom.: 0 Cov.: 33 AF XY: 0.0000671 AC XY: 5 AN XY: 74480

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000966 Hom.: 0

Bravo AF: 0.0000945

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000107 AC: 13

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 17, 2023	The c.2356G>A (p.V786I) alteration is located in exon 2 (coding exon 1) of the MLH3 gene. This alteration results from a G to A substitution at nucleotide position 2356, causing the valine (V) at amino acid position 786 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -

Colorectal cancer, hereditary nonpolyposis, type 7 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

MLH3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 03, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	1.7
Dann	Benign	0.90
DEOGEN2	Benign	0.079	T;.;.;T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.57	T;T;T;.
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.011	T;T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.1	L;L;.;L
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.14	N;.;N;N
REVEL	Benign	0.19
Sift	Benign	0.24	T;.;T;T
Sift4G	Benign	0.19	T;T;T;T
Polyphen		0.50	P;P;.;P
Vest4		0.049
MVP		0.74
MPC		0.081
ClinPred		0.024	T
GERP RS		2.0
Varity_R		0.021
gMVP		0.20

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: rs372089146; hg19: chr14-75514003;