rs201541505

Variant names:

• chr3-37025638-C-A
• rs201541505
• NM_000249.4:c.1040C>A

Your query was ambiguous. Multiple possible variants found:

• chr3-37025638-C-A
• chr3-37025638-C-G
• chr3-37025638-C-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 5P and 8B. PM1 PM5 PP3 BP6_Very_Strong

The NM_000249.4(MLH1):​c.1040C>A​(p.Thr347Asn) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T347A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 26)
  • Exomes 𝑓: 0.0025 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MLH1 NM_000249.4 missense, splice_region
• Scores: Splicing: ADA: 0.9916
• Clinical Significance: Benign reviewed by expert panel U:3 B:15
• Conservation: PhyloP100: 7.23
• Publications: 10 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: Likely_benign. The variant received -3 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 35 uncertain in NM_000249.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-37025638-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2691728.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 3-37025638-C-A is Benign according to our data. Variant chr3-37025638-C-A is described in ClinVar as Benign. ClinVar VariationId is 89629.Status of the report is reviewed_by_expert_panel, 3 stars.

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.1040C>A	p.Thr347Asn	missense splice_region	Exon 12 of 19	NP_000240.1	P40692-1
	MLH1	NM_001354628.2		c.1040C>A	p.Thr347Asn	missense splice_region	Exon 12 of 18	NP_001341557.1	A0A087WX20
	MLH1	NM_001354629.2		c.941C>A	p.Thr314Asn	missense splice_region	Exon 11 of 18	NP_001341558.1	A0AAQ5BGZ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH1	ENST00000231790.8	TSL:1 MANE Select	c.1040C>A	p.Thr347Asn	missense splice_region	Exon 12 of 19	ENSP00000231790.3	P40692-1
	MLH1	ENST00000456676.7	TSL:1	c.1040C>A	p.Thr347Asn	missense splice_region	Exon 12 of 17	ENSP00000416687.3	H0Y818
	MLH1	ENST00000413740.2	TSL:1	c.1040C>A	p.Thr347Asn	missense splice_region	Exon 12 of 15	ENSP00000416476.2	H0Y806

Frequencies

GnomAD3 genomes AF: 0.000258 AC: 30 AN: 116394 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.0000347

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00112

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.000434

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000280

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000547 AC: 10 AN: 182724 AF XY: 0.0000591

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: 0.000113

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00246 AC: 2056 AN: 835610 Hom.: 0 Cov.: 24 AF XY: 0.00230 AC XY: 968 AN XY: 420194

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

African (AFR) AF: 0.00330 AC: 54 AN: 16344

American (AMR) AF: 0.000431 AC: 11 AN: 25544

Ashkenazi Jewish (ASJ) AF: 0.00117 AC: 18 AN: 15434

East Asian (EAS) AF: 0.00174 AC: 36 AN: 20708

South Asian (SAS) AF: 0.00134 AC: 50 AN: 37228

European-Finnish (FIN) AF: 0.000207 AC: 8 AN: 38686

Middle Eastern (MID) AF: 0.00159 AC: 5 AN: 3136

European-Non Finnish (NFE) AF: 0.00280 AC: 1805 AN: 645480

Other (OTH) AF: 0.00209 AC: 69 AN: 33050

⚠️ 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: AS_VQSR AF: 0.000240 AC: 28 AN: 116424 Hom.: 0 Cov.: 26 AF XY: 0.000278 AC XY: 15 AN XY: 53878

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

African (AFR) AF: 0.0000347 AC: 1 AN: 28836

American (AMR) AF: 0.00 AC: 0 AN: 9426

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3218

East Asian (EAS) AF: 0.000560 AC: 2 AN: 3572

South Asian (SAS) AF: 0.00166 AC: 6 AN: 3604

European-Finnish (FIN) AF: 0.000434 AC: 2 AN: 4604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 124

European-Non Finnish (NFE) AF: 0.000280 AC: 17 AN: 60704

Other (OTH) AF: 0.00 AC: 0 AN: 1492

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000808314), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000117 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000660 AC: 8

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	6	not specified (7)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	2	1	not provided (3)
-	-	1	Colorectal cancer, hereditary nonpolyposis, type 2 (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	-	1	Lynch 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	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.2
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.65
Sift	Benign	0.073	T
Sift4G	Benign	0.12	T
Polyphen		0.60	P
Vest4		0.59
MVP		0.88
MPC		0.094
ClinPred		0.39	T
GERP RS		5.7
PromoterAI		-0.0020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.42
Mutation Taster		=29/71	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.73
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: rs201541505; hg19: chr3-37067129;