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