14-75048965-T-G

Variant names:

• chr14-75048965-T-G
• rs28756981
• NM_001040108.2:c.691A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001040108.2(MLH3):​c.691A>C​(p.Lys231Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0168 in 1,613,400 control chromosomes in the GnomAD database, including 289 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. K231E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.013 (18 hom., cov: 33)
  • Exomes 𝑓: 0.017 (271 hom.)
• Consequence: MLH3 NM_001040108.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.16
• Publications: 20 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=0.0039312243).
• BP6: Variant 14-75048965-T-G is Benign according to our data. Variant chr14-75048965-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0129 (1960/152328) while in subpopulation NFE AF = 0.0193 (1310/68026). AF 95% confidence interval is 0.0184. There are 18 homozygotes in GnomAd4. There are 970 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 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.691A>C	p.Lys231Gln	missense	Exon 2 of 13	NP_001035197.1
	MLH3	NM_014381.3		c.691A>C	p.Lys231Gln	missense	Exon 2 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.691A>C	p.Lys231Gln	missense	Exon 2 of 13	ENSP00000348020.2
	MLH3	ENST00000380968.6	TSL:1	c.691A>C	p.Lys231Gln	missense	Exon 2 of 12	ENSP00000370355.3
	MLH3	ENST00000930871.1		c.691A>C	p.Lys231Gln	missense	Exon 2 of 13	ENSP00000600930.1

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1960 AN: 152210 Hom.: 18 Cov.: 33

Gnomad AFR AF: 0.00381

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.0100

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0232

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0193

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.0121 AC: 3016 AN: 249362 AF XY: 0.0122

Gnomad AFR exome AF: 0.00291

Gnomad AMR exome AF: 0.00483

Gnomad ASJ exome AF: 0.00938

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0249

Gnomad NFE exome AF: 0.0186

Gnomad OTH exome AF: 0.0109

GnomAD4 exome AF: 0.0172 AC: 25160 AN: 1461072 Hom.: 271 Cov.: 35 AF XY: 0.0168 AC XY: 12199 AN XY: 726786

African (AFR) AF: 0.00234 AC: 78 AN: 33404

American (AMR) AF: 0.00563 AC: 251 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.00808 AC: 211 AN: 26114

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39688

South Asian (SAS) AF: 0.000709 AC: 61 AN: 86032

European-Finnish (FIN) AF: 0.0235 AC: 1254 AN: 53392

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5760

European-Non Finnish (NFE) AF: 0.0202 AC: 22439 AN: 1111730

Other (OTH) AF: 0.0142 AC: 857 AN: 60354

GnomAD4 genome AF: 0.0129 AC: 1960 AN: 152328 Hom.: 18 Cov.: 33 AF XY: 0.0130 AC XY: 970 AN XY: 74480

African (AFR) AF: 0.00380 AC: 158 AN: 41578

American (AMR) AF: 0.0100 AC: 153 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 36 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.0232 AC: 246 AN: 10610

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0193 AC: 1310 AN: 68026

Other (OTH) AF: 0.0109 AC: 23 AN: 2116

Alfa AF: 0.0171 Hom.: 100

Bravo AF: 0.0120

TwinsUK AF: 0.0186 AC: 69

ALSPAC AF: 0.0169 AC: 65

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.0192 AC: 165

ExAC AF: 0.0123 AC: 1488

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0177

EpiControl AF: 0.0169

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Colorectal cancer, hereditary nonpolyposis, type 7 (3)
-	-	3	not provided (3)
-	-	1	Colorectal cancer;C0476089:Endometrial carcinoma;C1858380:Colorectal cancer, hereditary nonpolyposis, type 7 (1)
-	-	1	Endometrial carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.093
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.2
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.20
Sift	Benign	0.26	T
Sift4G	Benign	0.24	T
Polyphen		0.53	P
Vest4		0.10
MPC		0.14
ClinPred		0.015	T
GERP RS		4.5
Varity_R		0.21
gMVP		0.45
Mutation Taster		=99/1	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: rs28756981; hg19: chr14-75515668; COSMIC: COSV104587310;