3-37048583-A-G

Variant names:

• chr3-37048583-A-G
• rs55907433
• NM_000249.4:c.1963A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000249.4(MLH1):​c.1963A>G​(p.Ile655Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000727 in 1,613,630 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 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. I655T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00051 (3 hom.)
• Consequence: MLH1 NM_000249.4 missense
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:29 O:1
• Conservation: PhyloP100: 1.92
• Publications: 25 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: ClinGen, Orphanet, G2P
• 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P, 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: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 18 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 30 uncertain in NM_000249.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.013260722).
• BP6: Variant 3-37048583-A-G is Benign according to our data. Variant chr3-37048583-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 41637.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00282 (429/152048) while in subpopulation AFR AF = 0.00863 (358/41476). AF 95% confidence interval is 0.00789. There are 1 homozygotes in GnomAd4. There are 203 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH1	NM_000249.4	MANE Select	c.1963A>G	p.Ile655Val	missense	Exon 17 of 19	NP_000240.1	P40692-1
	MLH1	NM_001354629.2		c.1864A>G	p.Ile622Val	missense	Exon 16 of 18	NP_001341558.1	A0AAQ5BGZ2
	MLH1	NM_001354630.2		c.1798A>G	p.Ile600Val	missense	Exon 16 of 18	NP_001341559.1	A0A669KAW3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH1	ENST00000231790.8	TSL:1 MANE Select	c.1963A>G	p.Ile655Val	missense	Exon 17 of 19	ENSP00000231790.3	P40692-1
	MLH1	ENST00000458205.6	TSL:1	c.1240A>G	p.Ile414Val	missense	Exon 18 of 20	ENSP00000402667.2	P40692-2
	MLH1	ENST00000456676.7	TSL:1	c.1896+900A>G		intron	N/A	ENSP00000416687.3	H0Y818

Frequencies

GnomAD3 genomes AF: 0.00282 AC: 429 AN: 151930 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00866

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000984

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00105 AC: 264 AN: 251262 AF XY: 0.000825

Gnomad AFR exome AF: 0.00935

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00734

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000880

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000509 AC: 744 AN: 1461582 Hom.: 3 Cov.: 31 AF XY: 0.000465 AC XY: 338 AN XY: 727100

African (AFR) AF: 0.00971 AC: 325 AN: 33468

American (AMR) AF: 0.000693 AC: 31 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00750 AC: 196 AN: 26134

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

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5766

European-Non Finnish (NFE) AF: 0.0000738 AC: 82 AN: 1111758

Other (OTH) AF: 0.00149 AC: 90 AN: 60390

GnomAD4 genome AF: 0.00282 AC: 429 AN: 152048 Hom.: 1 Cov.: 31 AF XY: 0.00273 AC XY: 203 AN XY: 74306

African (AFR) AF: 0.00863 AC: 358 AN: 41476

American (AMR) AF: 0.000983 AC: 15 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 39 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000177 AC: 12 AN: 67982

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00115 Hom.: 2

Bravo AF: 0.00309

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00931 AC: 41

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00105 AC: 127

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (8)
-	-	6	Colorectal cancer, hereditary nonpolyposis, type 2 (6)
-	-	6	Hereditary cancer-predisposing syndrome (6)
-	1	4	not provided (5)
-	-	2	Lynch syndrome (2)
-	-	1	Endometrial carcinoma (1)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	-	1	Muir-Torré syndrome (1)
-	-	1	Muir-Torré syndrome;C1333991:Colorectal cancer, hereditary nonpolyposis, type 2;C5399763:Mismatch repair cancer syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Uncertain	0.50	D
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.63
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.41	N
PhyloP100		1.9
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.17	N
REVEL	Uncertain	0.35
Sift	Benign	0.74	T
Sift4G	Benign	0.46	T
Polyphen		0.0	B
Vest4		0.82
MVP		0.90
MPC		0.058
ClinPred		0.0024	T
GERP RS		0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.047
gMVP		0.27
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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: rs55907433; hg19: chr3-37090074;