NM_001040108.2:c.2924A>G

Variant names:

• chr14-75046732-T-C
• rs141066164
• NM_001040108.2:c.2924A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_001040108.2(MLH3):​c.2924A>G​(p.Asn975Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000253 in 1,614,176 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 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. N975D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: MLH3 NM_001040108.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.182
• Publications: 3 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00404799).
• BP6: Variant 14-75046732-T-C is Benign according to our data. Variant chr14-75046732-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 238247.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 = 0.00145 (221/152316) while in subpopulation AFR AF = 0.00515 (214/41580). AF 95% confidence interval is 0.00458. There are 0 homozygotes in GnomAd4. There are 109 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.2924A>G	p.Asn975Ser	missense	Exon 2 of 13	NP_001035197.1
	MLH3	NM_014381.3		c.2924A>G	p.Asn975Ser	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.2924A>G	p.Asn975Ser	missense	Exon 2 of 13	ENSP00000348020.2
	MLH3	ENST00000380968.6	TSL:1	c.2924A>G	p.Asn975Ser	missense	Exon 2 of 12	ENSP00000370355.3
	MLH3	ENST00000556257.5	TSL:5	c.2924A>G	p.Asn975Ser	missense	Exon 2 of 7	ENSP00000451540.1

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 217 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000346 AC: 87 AN: 251178 AF XY: 0.000236

Gnomad AFR exome AF: 0.00481

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000128 AC: 187 AN: 1461860 Hom.: 1 Cov.: 34 AF XY: 0.000107 AC XY: 78 AN XY: 727224

African (AFR) AF: 0.00463 AC: 155 AN: 33480

American (AMR) AF: 0.000268 AC: 12 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111992

Other (OTH) AF: 0.000265 AC: 16 AN: 60396

GnomAD4 genome AF: 0.00145 AC: 221 AN: 152316 Hom.: 0 Cov.: 32 AF XY: 0.00146 AC XY: 109 AN XY: 74482

African (AFR) AF: 0.00515 AC: 214 AN: 41580

American (AMR) AF: 0.000327 AC: 5 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000709 Hom.: 0

Bravo AF: 0.00163

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000404 AC: 49

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Colorectal cancer, hereditary nonpolyposis, type 7 (2)
-	-	1	Colorectal cancer;C0476089:Endometrial carcinoma;C1858380:Colorectal cancer, hereditary nonpolyposis, type 7 (1)
-	-	1	MLH3-related disorder (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	0.056
DANN	Benign	0.47
DEOGEN2	Benign	0.092	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.18
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.099
Sift	Benign	0.24	T
Sift4G	Benign	0.56	T
Polyphen		0.0	B
Vest4		0.059
MVP		0.54
MPC		0.080
ClinPred		0.0053	T
GERP RS		-0.32
PromoterAI		-0.016	Neutral
Varity_R		0.025
gMVP		0.098
Mutation Taster		=100/0	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: rs141066164; hg19: chr14-75513435; COSMIC: COSV99032104; COSMIC: COSV99032104;