14-75039993-C-T

Variant names:

• chr14-75039993-C-T
• rs28757011
• NM_001040108.2:c.3488G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001040108.2(MLH3):​c.3488G>A​(p.Gly1163Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000721 in 1,591,542 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G1163G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 27)
  • Exomes 𝑓: 0.00067 (9 hom.)
• Consequence: MLH3 NM_001040108.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 1.90
• Publications: 9 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0056854784).
• BP6: Variant 14-75039993-C-T is Benign according to our data. Variant chr14-75039993-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 416458.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00118 (178/151282) while in subpopulation EAS AF = 0.026 (133/5122). AF 95% confidence interval is 0.0224. There are 0 homozygotes in GnomAd4. There are 90 alleles in the male GnomAd4 subpopulation. Median coverage is 27. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 AD,AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH3	NM_001040108.2	MANE Select	c.3488G>A	p.Gly1163Asp	missense	Exon 5 of 13	NP_001035197.1
	MLH3	NM_014381.3		c.3488G>A	p.Gly1163Asp	missense	Exon 5 of 12	NP_055196.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH3	ENST00000355774.7	TSL:5 MANE Select	c.3488G>A	p.Gly1163Asp	missense	Exon 5 of 13	ENSP00000348020.2
	MLH3	ENST00000380968.6	TSL:1	c.3488G>A	p.Gly1163Asp	missense	Exon 5 of 12	ENSP00000370355.3
	MLH3	ENST00000553713.5	TSL:5	c.557G>A	p.Gly186Asp	missense	Exon 3 of 11	ENSP00000451130.1

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 178 AN: 151168 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.000607

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00112

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0259

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000966

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000485

GnomAD2 exomes AF: 0.00218 AC: 548 AN: 251000 AF XY: 0.00187

Gnomad AFR exome AF: 0.000678

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0284

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000673 AC: 969 AN: 1440260 Hom.: 9 Cov.: 26 AF XY: 0.000638 AC XY: 458 AN XY: 717796

African (AFR) AF: 0.000394 AC: 13 AN: 32994

American (AMR) AF: 0.000135 AC: 6 AN: 44574

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25850

East Asian (EAS) AF: 0.0219 AC: 856 AN: 39016

South Asian (SAS) AF: 0.0000582 AC: 5 AN: 85886

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52504

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.00000548 AC: 6 AN: 1094248

Other (OTH) AF: 0.00140 AC: 83 AN: 59476

GnomAD4 genome AF: 0.00118 AC: 178 AN: 151282 Hom.: 0 Cov.: 27 AF XY: 0.00122 AC XY: 90 AN XY: 73844

African (AFR) AF: 0.000606 AC: 25 AN: 41276

American (AMR) AF: 0.00112 AC: 17 AN: 15138

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0260 AC: 133 AN: 5122

South Asian (SAS) AF: 0.00 AC: 0 AN: 4780

European-Finnish (FIN) AF: 0.0000966 AC: 1 AN: 10352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67862

Other (OTH) AF: 0.000480 AC: 1 AN: 2082

Alfa AF: 0.00102 Hom.: 7

Bravo AF: 0.00140

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00194 AC: 235

Asia WGS AF: 0.00751 AC: 26 AN: 3476

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not specified (3)
-	-	2	Colorectal cancer, hereditary nonpolyposis, type 7 (2)
-	-	1	Colorectal cancer;C1858380:Colorectal cancer, hereditary nonpolyposis, type 7 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.00061
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.85	L
PhyloP100		1.9
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.20
Sift	Benign	0.094	T
Sift4G	Benign	0.15	T
Polyphen		0.043	B
Vest4		0.20
MVP		0.81
MPC		0.17
ClinPred		0.033	T
GERP RS		3.7
Varity_R		0.41
gMVP		0.50
Mutation Taster		=90/10	polymorphism

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: rs28757011; hg19: chr14-75506696; COSMIC: COSV105867929;