rs28756992

chr14-75047123-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001040108.2(MLH3):c.2533A>G(p.Ser845Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,614,184 control chromosomes in the GnomAD database, including 146 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S845N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.015 (32 hom., cov: 32)
  • Exomes 𝑓: 0.0098 (114 hom.)
• Consequence: MLH3 NM_001040108.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.182

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028146803).
• BP6: Variant 14-75047123-T-C is Benign according to our data. Variant chr14-75047123-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 220674.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0148 (2259/152354) while in subpopulation AFR AF= 0.0316 (1315/41584). AF 95% confidence interval is 0.0302. There are 32 homozygotes in gnomad4. There are 1084 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 2258 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLH3	NM_001040108.2	c.2533A>G	p.Ser845Gly	missense_variant	2/13	ENST00000355774.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLH3	ENST00000355774.7	c.2533A>G	p.Ser845Gly	missense_variant	2/13	5	NM_001040108.2	P1
MLH3	ENST00000380968.6	c.2533A>G	p.Ser845Gly	missense_variant	2/12	1
MLH3	ENST00000556257.5	c.2533A>G	p.Ser845Gly	missense_variant	2/7	5
MLH3	ENST00000555671.1	n.79A>G		non_coding_transcript_exon_variant	1/2	5

Frequencies

GnomAD3 genomes AF: 0.0148 AC: 2258 AN: 152236 Hom.: 32 Cov.: 32

Gnomad AFR AF: 0.0317

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.00949

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.0102

Gnomad SAS AF: 0.0277

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00788

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.0109 AC: 2746 AN: 251264 Hom.: 27 AF XY: 0.0116 AC XY: 1579 AN XY: 135838

Gnomad AFR exome AF: 0.0306

Gnomad AMR exome AF: 0.00610

Gnomad ASJ exome AF: 0.00208

Gnomad EAS exome AF: 0.0122

Gnomad SAS exome AF: 0.0280

Gnomad FIN exome AF: 0.00152

Gnomad NFE exome AF: 0.00735

Gnomad OTH exome AF: 0.0114

GnomAD4 exome AF: 0.00982 AC: 14362 AN: 1461830 Hom.: 114 Cov.: 34 AF XY: 0.0102 AC XY: 7442 AN XY: 727210

Gnomad4 AFR exome AF: 0.0349

Gnomad4 AMR exome AF: 0.00639

Gnomad4 ASJ exome AF: 0.00295

Gnomad4 EAS exome AF: 0.0101

Gnomad4 SAS exome AF: 0.0267

Gnomad4 FIN exome AF: 0.00155

Gnomad4 NFE exome AF: 0.00833

Gnomad4 OTH exome AF: 0.0111

GnomAD4 genome AF: 0.0148 AC: 2259 AN: 152354 Hom.: 32 Cov.: 32 AF XY: 0.0145 AC XY: 1084 AN XY: 74516

Gnomad4 AFR AF: 0.0316

Gnomad4 AMR AF: 0.00948

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.0102

Gnomad4 SAS AF: 0.0280

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.00788

Gnomad4 OTH AF: 0.0151

Alfa AF: 0.00918 Hom.: 35

Bravo AF: 0.0158

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.00960 AC: 37

ESP6500AA AF: 0.0322 AC: 142

ESP6500EA AF: 0.00663 AC: 57

ExAC AF: 0.0116 AC: 1410

Asia WGS AF: 0.0190 AC: 66 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 30, 2020	This alteration is classified as 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. -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The MLH3 p.Ser845Gly variant was identified in 5 of 934 proband chromosomes (frequency: 0.005) from individuals or families with colorectal cancer and was also present in 8 of 994 control chromosomes (frequency: 0.008) from healthy individuals (de Jong_2004_PMID:15193445). The variant was identified in dbSNP (ID: rs28756992), ClinVar (classified as likely benign by Illumina and as benign by Invitae for Lynch syndrome) and LOVD 3.0 (classified as a VUS) but was not identified in Cosmic. The variant was identified in control databases in 3189 of 282666 chromosomes (38 homozygous) at a frequency of 0.011282 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: African in 791 of 24898 chromosomes (freq: 0.03177), South Asian in 856 of 30612 chromosomes (freq: 0.02796), East Asian in 240 of 19952 chromosomes (freq: 0.01203), Other in 76 of 7214 chromosomes (freq: 0.01054), European (non-Finnish) in 950 of 129064 chromosomes (freq: 0.007361), Latino in 217 of 35438 chromosomes (freq: 0.006123), Ashkenazi Jewish in 22 of 10368 chromosomes (freq: 0.002122), and European (Finnish) in 37 of 25120 chromosomes (freq: 0.001473). The p.Ser845 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. 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 this variant meets our laboratory's criteria to be classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Colorectal cancer, hereditary nonpolyposis, type 7 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	0.29
Dann	Benign	0.61
DEOGEN2	Benign	0.092	T;.;.;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.52	T;T;T;.
MetaRNN	Benign	0.0028	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.69	N;N;.;N
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.2	N;.;N;N
REVEL	Benign	0.20
Sift	Benign	0.57	T;.;T;T
Sift4G	Benign	0.95	T;T;T;T
Polyphen		0.0	B;B;.;B
Vest4		0.047
MPC		0.091
ClinPred		0.0026	T
GERP RS		-7.2
Varity_R		0.034
gMVP		0.18

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: rs28756992; hg19: chr14-75513826; COSMIC: COSV104587544; COSMIC: COSV104587544;