14-75048943-T-G

Position:

• chr14-75048943-T-G

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.713A>C​(p.Tyr238Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000454 in 1,613,242 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00045 (4 hom.)
• Consequence: MLH3 NM_001040108.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 2.18

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02066508).
• BP6: Variant 14-75048943-T-G is Benign according to our data. Variant chr14-75048943-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 238252.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00045 (657/1460982) while in subpopulation MID AF= 0.00191 (11/5758). AF 95% confidence interval is 0.00107. There are 4 homozygotes in gnomad4_exome. There are 358 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 76 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLH3	NM_001040108.2	c.713A>C	p.Tyr238Ser	missense_variant	2/13	ENST00000355774.7	NP_001035197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLH3	ENST00000355774.7	c.713A>C	p.Tyr238Ser	missense_variant	2/13	5	NM_001040108.2	ENSP00000348020.2
MLH3	ENST00000380968.6	c.713A>C	p.Tyr238Ser	missense_variant	2/12	1		ENSP00000370355.3
MLH3	ENST00000556257.5	c.713A>C	p.Tyr238Ser	missense_variant	2/7	5		ENSP00000451540.1

Frequencies

GnomAD3 genomes AF: 0.000499 AC: 76 AN: 152260 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000964

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000816 AC: 204 AN: 249962 Hom.: 3 AF XY: 0.000872 AC XY: 118 AN XY: 135276

Gnomad AFR exome AF: 0.0000624

Gnomad AMR exome AF: 0.000320

Gnomad ASJ exome AF: 0.0153

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000986

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000203

Gnomad OTH exome AF: 0.00198

GnomAD4 exome AF: 0.000450 AC: 657 AN: 1460982 Hom.: 4 Cov.: 35 AF XY: 0.000493 AC XY: 358 AN XY: 726760

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.000359

Gnomad4 ASJ exome AF: 0.0151

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000198

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000123

Gnomad4 OTH exome AF: 0.00133

GnomAD4 genome AF: 0.000499 AC: 76 AN: 152260 Hom.: 0 Cov.: 33 AF XY: 0.000444 AC XY: 33 AN XY: 74392

Gnomad4 AFR AF: 0.0000964

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.0135

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00143

Alfa AF: 0.000899 Hom.: 2

Bravo AF: 0.000536

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000675 AC: 82

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.000416

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 25, 2020	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Colorectal cancer, hereditary nonpolyposis, type 7 Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The MLH3 p.Tyr238Ser variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs144707485) and in ClinVar (classified as uncertain significance by Illumina Clinical Services Laboratory for Lynch syndrome and likely benign by Invitae for MLH3-Related Lynch syndrome). The variant was identified in control databases in 209 of 281376 chromosomes (3 homozygous) at a frequency of 0.000743 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 154 of 10324 chromosomes (freq: 0.01492), Other in 14 of 7150 chromosomes (freq: 0.001958), Latino in 11 of 35232 chromosomes (freq: 0.000312), European (non-Finnish) in 26 of 128544 chromosomes (freq: 0.000202), South Asian in 3 of 30418 chromosomes (freq: 0.000099), African in 1 of 24738 chromosomes (freq: 0.00004), but was not observed in the East Asian or European (Finnish) populations. Although the p.Tyr238 residue is not conserved in mammals and other organisms, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

MLH3-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 14, 2024

This variant is classified as 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	Uncertain	0.42
BayesDel_addAF	Benign	0.0043	T
BayesDel_noAF	Uncertain	0.070
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.64	D;.;.;D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.82	T;T;T;.
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.021	T;T;T;T
MetaSVM	Uncertain	0.48	D
MutationAssessor	Uncertain	2.5	M;M;.;M
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-6.8	D;.;D;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0040	D;.;D;D
Sift4G	Uncertain	0.0070	D;D;D;D
Polyphen		0.99	D;D;.;D
Vest4		0.49
MVP		0.93
MPC		0.57
ClinPred		0.11	T
GERP RS		4.5
Varity_R		0.68
gMVP		0.77

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: rs144707485; hg19: chr14-75515646; COSMIC: COSV99465128; COSMIC: COSV99465128;