NM_058216.3:c.431T>C (p.Ile144Thr) in RAD51C is a rare missense variant with extremely low population frequency (gnomAD v2.1 AF=0.0057%, v4.1 AF=0.014%). The ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel has published RAD51C specifications (version 1.0.0) but no per-criterion rules were available for direct application; generic ACMG/AMP 2015 criteria were used as fallback.1 The variant is absent or at extremely low frequency in population databases, meeting PM2 at supporting strength (gnomAD v4.1 overall AF=0.014%; 0 homozygotes). gnomAD v4.1 Middle Eastern subpopulation AF=0.279% is noted but remains below the BS1 threshold of 0.3%.2 Myriad Genetics classified this variant as Likely benign (SCV004019909, criteria provided), meeting BP6 at supporting strength. However, the cited reference (PMID:25085752) is a BRCA1/BRCA2 reclassification algorithm and does not provide RAD51C-specific evidence.3 In silico predictions are inconclusive: REVEL 0.314, BayesDel 0.041, SpliceAI delta 0.01, with Polyphen-2/SIFT suggesting possible damage but SNPs&GO predicting neutrality (PMID:23117857). Neither PP3 nor BP4 is met.4 The variant has been observed in one Iraqi Jewish breast cancer proband (PMID:23117857) and one Danish HBOC family (PMID:26740214) but at insufficient frequency for PS4. No functional studies (PS3/BS3), segregation data (PP1/BS4), or de novo observations (PS2/PM6) are available.5 The variant is not located in a statistically significant hotspot (PM1 not met), no alternative nucleotide changes at the same residue are established as pathogenic (PM5 not applicable), and RAD51C is not a gene with a low rate of benign missense variation (PP2 not met).6 Overall classification: Uncertain significance. One supporting pathogenic criterion (PM2) is balanced by one supporting benign criterion (BP6), with all other criteria either not met or not applicable. This results in indeterminate classification under ACMG/AMP 2015 combination rules.7
RAD51C
Final classification
VUS
PM2BP6
RAD51C
c.431T>C
p.Ile144Thr
This variant
NM_058216.3:c.431T>C (p.Ile144Thr) in RAD51C is a rare missense variant with extremely low population frequency (gnomAD v2.1 AF=0.0057%, v4.1 AF=0.014%). The ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel has published RAD51C specifications (version 1.0.0) but no per-criterion rules were available for direct application; generic ACMG/AMP 2015 criteria were used as fallback.
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RAD51C Version 1.0.0 v1.0.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP6 supporting; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP6
VUS
RAD51C c.431T>C
PM2 + BP6
→
VUS
Gene diagram
· NM_058216.3 · variants mapped to exon structure
RAD51C
NM_058216.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 18 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
NM_058216.3:c.431T>C is at extremely low frequency in population databases. gnomAD v2.1: AF=0.00566% (16/282,878 alleles, 0 homozygotes). gnomAD v4.1: AF=0.01419% (229/1,614,096 alleles, 0 homozygotes). Both overall frequencies are well below the 0.1% threshold. No homozygotes observed. Note: gnomAD v4.1 grpmax FAF=0.178% and Middle Eastern subpopulation AF=0.279%, which slightly moderates the strength but remains below the BS1 threshold of 0.3%.
gnomAD v2.1 AF=0.00566% (16/282878)gnomAD v4.1 AF=0.01419% (229/1
✓
BP6
supporting
Benign
Myriad Genetics, Inc. (SCV004019909) classified this variant as Likely benign with criteria provided. This represents a reputable clinical laboratory asserting a benign interpretation. While only a single submitter, it meets BP6 at supporting level.
Myriad GeneticsInc. classified as Likely benign (SCV004019909criteria provided).
Assessed · not applied
· 18 not met · 0 not assessed
Pathogenic
PS1
No evidence that the same amino acid change (p.Ile144Thr) has been established as pathogenic via a different nucleotide change.
PS2
No de novo observation (maternity and paternity confirmed) has been reported for NM_058216.3:c.431T>C in any reviewed publication or ClinVar submission.
PS3
No variant-specific functional studies (e.g., HR assay, protein interaction, cellular sensitivity) have been reported for p.Ile144Thr in any reviewed publication.
PS4
The variant has been observed in affected individuals but at insufficient frequency and without controlled case-control comparison to reach statistical significance.
PM1
p.Ile144 is not located in a statistically significant mutational hotspot or a well-established critical functional domain for RAD51C.
PM6
No de novo observation with confirmed maternity and paternity has been reported for this variant.
PP1
No segregation data available.
PP2
RAD51C is not established as a gene with a low rate of benign missense variation.
PP3
In silico predictions are mixed and do not converge on a damaging effect.
PP5
No reputable source (e.g., expert panel, clinical laboratory with multi-criteria review) has classified this variant as pathogenic or likely pathogenic.
Benign
BA1
The variant is not common.
BS1
The variant does not exceed the 0.3% population frequency threshold.
BS2
No homozygous individuals observed in gnomAD v2.1 (0/282,878) or gnomAD v4.1 (0/1,614,096).
BS3
No functional studies have been reported demonstrating that p.Ile144Thr has no deleterious effect on protein function or splicing.
BS4
No segregation data available to demonstrate lack of co-segregation with disease.
BP2
No data available on observation of this variant in trans with a known pathogenic RAD51C variant.
BP4
Multiple lines of in silico evidence are not consistently benign.
BP5
No data available.
N/A · 6
PVS1 · PM5 · PP4 · BP1 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.000141875; MAF= 0.01419%, 229/1614096 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.00279421; MAF= 0.27942%, 17/6084 alleles, homozygotes = 0); grpmax FAF= 0.0017798.
v2.1
This variant is present in gnomAD v2.1 (AF= 5.65615e-05; MAF= 0.00566%, 16/282878 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000240308; MAF= 0.02403%, 6/24968 alleles, homozygotes = 0); grpmax FAF= 0.00015629.
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.014%
· 229 / 1,614,096
0 hom · FAF 0.18%
0 hom · FAF 0.18%
Middle Eastern 17 / 6,084 |
0.28% |
African/African American 15 / 74,944 |
0.02% |
European (non-Finnish) 186 / 1,180,046 |
0.016% |
Remaining individuals 7 / 62,484 |
0.011% |
Admixed American 3 / 60,004 |
0.005% |
South Asian 1 / 91,090 |
0.0011% |
+ 4 not observed (European (Finnish), Amish, East Asian, Ashkenazi Jewish)
gnomAD v2.1
0.0057%
· 16 / 282,878
0 hom · FAF 0.016%
0 hom · FAF 0.016%
African/African American 6 / 24,968 |
0.024% |
European (non-Finnish) 10 / 129,184 |
0.0077% |
+ 6 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (18 clinical laboratories) and as Likely benign (1 clinical laboratory). (ClinVarID = 142840)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.314. BayesDel score = 0.0405109.
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. RAD51C, a DNA repair protein, is altered by mutation or deletion in certain breast cancers.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
9Sources
Triaged references · 8 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
26261251 ↗
Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population.
CLINVAR
26740214 ↗
Identification of six pathogenic RAD51C mutations via mutational screening of 1228 Danish individuals with increased risk of hereditary breast and/or ovarian cancer.
CLINVAR
36099300 ↗
Homologous recombination-deficient mutation cluster in tumor suppressor RAD51C identified by comprehensive analysis of cancer variants.
CLINVAR
21537932 ↗
A HRM-based screening method detects RAD51C germ-line deleterious mutations in Spanish breast and ovarian cancer families.
CLINVAR
25186627 ↗
Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel.
CLINVAR