3-37025655-G-T

Variant names:

• chr3-37025655-G-T
• rs1412018144
• NM_000249.4:c.1057G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000249.4(MLH1):​c.1057G>T​(p.Ala353Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000297 in 1,347,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A353G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0000030 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MLH1 NM_000249.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.19
• Publications: 6 publications found

Genes affected

MLH1 (HGNC:7127): (mutL homolog 1) The protein encoded by this gene can heterodimerize with mismatch repair endonuclease PMS2 to form MutL alpha, part of the DNA mismatch repair system. When MutL alpha is bound by MutS beta and some accessory proteins, the PMS2 subunit of MutL alpha introduces a single-strand break near DNA mismatches, providing an entry point for exonuclease degradation. The encoded protein is also involved in DNA damage signaling and can heterodimerize with DNA mismatch repair protein MLH3 to form MutL gamma, which is involved in meiosis. This gene was identified as a locus frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). [provided by RefSeq, Aug 2017]

MLH1 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
• Lynch syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp
• Muir-Torre syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, G2P, Orphanet
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• Lynch syndrome 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• ovarian cancer

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 30 uncertain in NM_000249.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14976963).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000249.4. 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
	MLH1	NM_000249.4	MANE Select	c.1057G>T	p.Ala353Ser	missense	Exon 12 of 19	NP_000240.1
	MLH1	NM_001354628.2		c.1057G>T	p.Ala353Ser	missense	Exon 12 of 18	NP_001341557.1
	MLH1	NM_001354629.2		c.958G>T	p.Ala320Ser	missense	Exon 11 of 18	NP_001341558.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH1	ENST00000231790.8	TSL:1 MANE Select	c.1057G>T	p.Ala353Ser	missense	Exon 12 of 19	ENSP00000231790.3
	MLH1	ENST00000456676.7	TSL:1	c.1057G>T	p.Ala353Ser	missense	Exon 12 of 17	ENSP00000416687.3
	MLH1	ENST00000413740.2	TSL:1	c.1057G>T	p.Ala353Ser	missense	Exon 12 of 15	ENSP00000416476.2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 133162 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 222568 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000297 AC: 4 AN: 1347938 Hom.: 0 Cov.: 33 AF XY: 0.00000450 AC XY: 3 AN XY: 666286

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30404

American (AMR) AF: 0.0000259 AC: 1 AN: 38638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23302

East Asian (EAS) AF: 0.00 AC: 0 AN: 34672

South Asian (SAS) AF: 0.00 AC: 0 AN: 65332

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5208

European-Non Finnish (NFE) AF: 0.00000286 AC: 3 AN: 1047236

Other (OTH) AF: 0.00 AC: 0 AN: 54550

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 133162 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 63100

African (AFR) AF: 0.00 AC: 0 AN: 33890

American (AMR) AF: 0.00 AC: 0 AN: 12028

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3378

East Asian (EAS) AF: 0.00 AC: 0 AN: 4558

South Asian (SAS) AF: 0.00 AC: 0 AN: 4304

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6926

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 194

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65290

Other (OTH) AF: 0.00 AC: 0 AN: 1706

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	9.9
DANN	Benign	0.88
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.36	N
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	0.51	N
PhyloP100		1.2
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.010	N
REVEL	Uncertain	0.58
Sift	Benign	0.64	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.22
MutPred		0.33		Gain of glycosylation at A353 (P = 0.0108)
MVP		0.96
MPC		0.061
ClinPred		0.029	T
GERP RS		1.8
PromoterAI		0.0021	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.037
gMVP		0.14
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1412018144; hg19: chr3-37067146;