NM_001276270.2:c.1024T>C

MBD4 · NP_001263199.1:p.(Ser342Pro) · NM_001276270.2

GRCh37: chr3:129155463 A>G · GRCh38: chr3:129436620 A>G

Gene: MBD4 Transcript: NM_001276270.2

Final call

Benign

BA1 stand-alone benign BS1 strong benign BP4 supporting benign

Variant details

Gene

MBD4

Transcript

NM_001276270.2

Protein

NP_001263199.1:p.(Ser342Pro)

gnomAD AF

0.014657520327721784 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

This variant has been reported in ClinVar as Benign by five clinical laboratories (ClinVar variation ID 1268570).

Multiple in silico tools predict a benign effect: REVEL score 0.285, BayesDel score -0.438, SpliceAI max delta score 0.03 (BP4 supporting).

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.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Benign classification because either BA1 is met or at least two strong benign criteria are present.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This is a missense variant (p.Ser342Pro), not a null variant (nonsense, frameshift, or canonical splice). The PVS1 variant assessment confirms the variant does not fall into any default null-variant bucket; generic PVS1 framework is not applicable.	pvs1_variant_assessment pvs1_gene_context pvs1_generic_framework
PS1	Not met	No alternative nucleotide change at codon 342 resulting in the same amino acid substitution (p.Ser342Pro) has been reported as pathogenic. No PS1-eligible comparator was identified.
PS2	Not met	No de novo observation has been reported for this variant. No maternity/paternity-confirmed de novo data are available in ClinVar submissions or the literature.
PS3	Not met	No well-established functional studies have directly tested this variant or a systematically characterized range that includes residue 342. OncoKB found no variant-specific reviewed functional evidence. The in silico scores (REVEL=0.285, BayesDel=-0.438) are computational predictors, not experimental functional data, and do not satisfy PS3 requirements.	oncokb revel bayesdel
PS4	Not met	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). Its prevalence in cases is not enriched relative to controls; population data strongly argue against pathogenicity.	gnomad_v2 gnomad_v4
PS5	Not met	No reputable source has reported this variant as pathogenic. ClinVar classifies it as Benign (5 clinical laboratories, variation ID 1268570).	clinvar
PM1	Not met	Residue S342 is not located in a known critical functional domain of MBD4. The methyl-CpG binding domain (MBD) spans approximately amino acids 82-147 and the DNA glycosylase domain spans approximately amino acids 426-580. S342 lies in the interdomain region with no established domain-level critical function. The cancerhotspots.org database does not identify this residue as a statistically significant hotspot.
PM2	Not met	This variant is present at high frequency in gnomAD. v2.1 AF=2.57% and v4.1 AF=1.47% far exceed the PM2 threshold of <0.1% for non-VCEP framework.	gnomad_v2 gnomad_v4
PM5	Not met	No same-residue pathogenic comparator variants were identified. The PM5 candidate search found no ClinVar variants at codon 342 with a different missense change classified as pathogenic or likely pathogenic.	pm5_candidates
PM6	Not met	No de novo observation has been reported for this variant. No maternity/paternity-confirmed de novo data are available.
PP1	Not assessed	No segregation data are available for this variant. No family studies have been reported in the literature or ClinVar submissions.
PP2	Not met	MBD4 tolerates missense variation, as evidenced by the high population frequency of this missense variant (AF=2.57% in gnomAD v2.1, 413 homozygotes). The gene does not have a low rate of benign missense variation as required by PP2.	gnomad_v2
PP3	Not met	Multiple lines of in silico evidence predict a benign effect. REVEL score is 0.285 (below the 0.5 threshold), BayesDel score is -0.438 (negative score predicts benign), and SpliceAI delta score is 0.03 (no predicted splicing impact). Computational evidence does not support a deleterious effect.	revel bayesdel spliceai
PP4	Not assessed	No patient phenotype or family history data are available for evaluation against a disease-specific presentation.
PP5	Not met	ClinVar review status is 'criteria provided, single submitter' (1-star), not the required 3-star expert panel for PP5 application. In any case, ClinVar classifies this variant as Benign, not Pathogenic.	clinvar
BA1	Met	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 gnomad_v4
BS1	Met	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 gnomad_v4
BS2	Not met	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. The homozygote count is more appropriately captured by BA1 frequency-based evidence.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established functional studies demonstrating no damaging effect are available for this variant. In silico predictors (REVEL=0.285, BayesDel=-0.438) provide computational evidence of benign effect but do not constitute well-established functional studies as required by BS3.	revel bayesdel
BS4	Not assessed	No segregation data are available for evaluation. No family studies with affected and unaffected members have been reported.
BP1	Not met	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. The literature describes primarily LOF truncating variants, but the spectrum of pathogenic missense variants has not been comprehensively established to satisfy BP1.	pvs1_gene_context
BP2	Not assessed	No data on observation in trans with a pathogenic variant are available. No phase information is reported.
BP4	Met	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 bayesdel spliceai
BP5	Not assessed	No data are available regarding an alternate molecular basis for disease in a case harboring this variant. No patient-level data were reviewed.
BP6	Not met	ClinVar review status is 'criteria provided, single submitter' (1-star). The PP5/BP6 framework rule requires a 3-star expert panel review status for supporting-strength application. Although 5 clinical laboratories classify this variant as Benign, the review status does not meet the 3-star threshold.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants with no predicted splice impact. This is a missense variant (c.1024T>C, p.Ser342Pro), not a synonymous variant.
BP3	N/A	BP3 applies to in-frame deletions or insertions in a repetitive region without a known function. This is a missense substitution, not an in-frame indel.
PM3	N/A	PM3 is for recessive disorders (variant detected in trans with a pathogenic variant). MBD4-related tumor predisposition is an autosomal dominant disorder; PM3 is not applicable.
PM4	N/A	PM4 applies to non-repeat in-frame deletions/insertions or stop-loss variants. This is a missense substitution, not an in-frame indel or stop-loss variant.

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