NM_001276270.2:c.1024T>C (p.Ser342Pro) in MBD4 is classified as Benign. This variant has an allele frequency of 2.57% in gnomAD v2.1 (7258/282704 alleles, 413 homozygotes) and 1.47% in gnomAD v4.1 (23658/1614052 alleles, 1294 homozygotes), exceeding the stand-alone benign BA1 threshold of >1% (non-VCEP). The grpmax filtering AF is 12.07% in the African/African American population (v2.1).1 This variant has been reported in ClinVar as Benign by five clinical laboratories (ClinVar variation ID 1268570).2 Multiple in silico tools predict a benign effect: REVEL score 0.285, BayesDel score -0.438, SpliceAI max delta score 0.03 (BP4 supporting).3 No functional studies, segregation data, or de novo observations are available for this variant. No publications specifically mention NM_001276270.2:c.1024T>C. PVS1 is not applicable as this is a missense variant, not a null variant.4
MBD4
Final classification
Benign
MBD4 c.1024T>C · p.Ser342Pro
MBD4
NM_001276270.2:c.1024T>C (p.Ser342Pro) in MBD4 is classified as Benign.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BA1 stand-alone benign, BS1 strong benign, BP4 supporting benign; combination = 1 stand-alone benign + 1 strong benign + 1 supporting benign, which maps to Benign.
Classification rationale
BA1BS1BP4
Benign
MBD4 c.1024T>C
BA1 + BS1 + BP4
→
Benign
Gene diagram
· NM_001276270.2 · variants mapped to exon structure
MBD4
NM_001276270.2
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 20 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
BA1
stand-alone
Benign
This variant has an allele frequency far exceeding 1% in gnomAD. v2.1 total AF=2.57% (7258/282704 alleles, 413 homozygotes), v4.1 total AF=1.47% (23658/1614052 alleles, 1294 homozygotes), with a grpmax filtering AF of 12.07% in the African/African American population (v2.1) and 12.45% (v4.1). This frequency is incompatible with a rare Mendelian disease-causing variant.
gnomAD v2.1 AF=2.57%413 homozygotesgrpmax FAF=12.07% (AFR)
✓
BS1
strong
Benign
This variant has an allele frequency far exceeding 0.3% in gnomAD. v2.1 total AF=2.57%, v4.1 total AF=1.47%. This population frequency is greater than expected for a rare disease-causing variant. Note: the frequency evidence is also captured at the higher BA1 threshold.
gnomAD v2.1 AF=2.57%v4.1 AF=1.47%. Both exceed the 0.3% BS1 threshold.
✓
BP4
supporting
Benign
Multiple lines of computational evidence predict no significant impact. REVEL score is 0.285 (predicts benign), BayesDel score is -0.438 (predicts benign), and SpliceAI delta score is 0.03 (predicts no splicing impact). Three independent in silico tools concordantly predict a benign effect.
REVEL=0.285 (benign)BayesDel=-0.438 (benign)SpliceAI max delta=0.03 (no splicing impact). Concordant benign prediction across three independent tools.
Assessed · not applied
Pathogenic
PS1
No alternative nucleotide change at codon 342 resulting in the same amino acid substitution (p.Ser342Pro) has been reported as pathogenic.
PS2
No de novo observation has been reported for this variant.
PS3
No well-established functional studies have directly tested this variant or a systematically characterized range that includes residue 342.
PS4
This variant is common in the general population (gnomAD AF=2.57% in v2.1, 1.47% in v4.1, grpmax FAF=12.07% in AFR).
PM1
Residue S342 is not located in a known critical functional domain of MBD4.
PM2
This variant is present at high frequency in gnomAD.
PM5
No same-residue pathogenic comparator variants were identified.
PM6
No de novo observation has been reported for this variant.
PP1
No segregation data are available for this variant.
PP2
MBD4 tolerates missense variation, as evidenced by the high population frequency of this missense variant (AF=2.57% in gnomAD v2.1, 413 homozygotes).
PP3
Multiple lines of in silico evidence predict a benign effect.
PP4
No patient phenotype or family history data are available for evaluation against a disease-specific presentation.
PP5
ClinVar review status is 'criteria provided, single submitter' (1-star), not the required 3-star expert panel for PP5 application.
Benign
BS2
Although 413 homozygotes are observed in gnomAD v2.1 (and 1294 in v4.1), MBD4-related tumor predisposition syndrome is an adult-onset cancer predisposition disorder that does not have full penetrance expected at an early age, as required by BS2.
BS3
No well-established functional studies demonstrating no damaging effect are available for this variant.
BS4
No segregation data are available for evaluation.
BP1
While pathogenic germline MBD4 variants include truncating mutations, there is insufficient evidence to conclude that missense variants are never or rarely disease-causing for this gene.
BP2
No data on observation in trans with a pathogenic variant are available.
BP5
No data are available regarding an alternate molecular basis for disease in a case harboring this variant.
BP6
ClinVar review status is 'criteria provided, single submitter' (1-star).
N/A · 5
PVS1 · PM3 · PM4 · BP3 · BP7
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.0146575; MAF= 1.46575%, 23658/1614052 alleles, homozygotes = 1294) and has highest observed frequency in the African/African American population (AF= 0.126587; MAF= 12.65867%, 9494/75000 alleles, homozygotes = 620); grpmax FAF= 0.124457.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.0256735; MAF= 2.56735%, 7258/282704 alleles, homozygotes = 413) and has highest observed frequency in the African/African American population (AF= 0.124048; MAF= 12.40478%, 3094/24942 alleles, homozygotes = 197); grpmax FAF= 0.120667.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.01992399565689468, 367/18420 alleles, homozygotes = 19).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
1.5%
· 23658 / 1,614,052
1294 hom · FAF 12%
1294 hom · FAF 12%
African/African American 9494 / 75,000 |
13% 620 hom |
South Asian 9466 / 91,080 |
10% 618 hom |
Remaining individuals 1088 / 62,506 |
1.7% 39 hom |
East Asian 690 / 44,862 |
1.5% 9 hom |
Middle Eastern 63 / 6,062 |
1% 2 hom |
Admixed American 539 / 60,018 |
0.9% 5 hom |
European (non-Finnish) 2295 / 1,179,986 |
0.19% 1 hom |
European (Finnish) 20 / 64,024 |
0.031% |
Ashkenazi Jewish 3 / 29,602 |
0.01% |
+ 1 not observed (Amish)
gnomAD v2.1
2.6%
· 7258 / 282,704
413 hom · FAF 12%
413 hom · FAF 12%
African/African American 3094 / 24,942 |
12% 197 hom |
South Asian 3255 / 30,612 |
11% 208 hom |
East Asian 310 / 19,954 |
1.6% 3 hom |
Remaining individuals 82 / 7,214 |
1.1% 3 hom |
Admixed American 210 / 35,428 |
0.59% 2 hom |
European (non-Finnish) 300 / 129,070 |
0.23% |
European (Finnish) 5 / 25,114 |
0.02% |
Ashkenazi Jewish 2 / 10,370 |
0.019% |
gnomAD Canada 🇨🇦
2%
· 367 / 18,420
19 hom · FAF 12%
19 hom · FAF 12%
African/African American 139 / 1,020 |
14% 12 hom |
South Asian 164 / 1,362 |
12% 5 hom |
Remaining individuals 19 / 1,136 |
1.7% |
East Asian 21 / 1,338 |
1.6% 2 hom |
Latino/Admixed American 5 / 838 |
0.6% |
European (non-Finnish) 19 / 11,742 |
0.16% |
+ 3 not observed (Ashkenazi Jewish, European (Finnish), Middle Eastern)
ClinVar
This variant has been reported in ClinVar as Benign (5 clinical laboratories). (ClinVarID = 1268570)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.285. BayesDel score = -0.437821.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MBD4, a DNA glycosylase, is infrequently altered in cancer.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV105073110, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 2 PMIDs not cited in assessment
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR