NM_000051.3:c.5544T>C (NP_000042.3:p.(Asp1848=)) is a synonymous variant in ATM exon 36, assessed using the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer (HBOP) Expert Panel specifications for ATM v1.5.0.

The variant is absent or exceedingly rare in population databases: gnomAD v4.1 global allele frequency 6.20×10⁻⁷ (1/1,613,962 alleles, 0 homozygotes) and gnomAD v2.1 allele frequency 7.97×10⁻⁶ (2/251,006 alleles, 0 homozygotes), satisfying PM2_Supporting (≤0.001% cutoff).

SpliceAI predicts no significant splicing impact (max delta = 0.06), satisfying BP4_Supporting (SpliceAI ≤0.1 for no predicted splicing impact) under the CSPEC HBOP splicing rule.

BP7_Supporting is applied: the variant is a synonymous substitution located at c.5544, which lies 18 nucleotides from the donor splice site (beyond the +7 boundary) and 153 nucleotides from the acceptor splice site (beyond the -21 boundary), meeting the CSPEC definition for synonymous variants outside donor/acceptor site boundaries.

REVEL, BayesDel, and HCI Prior scores are not available for this synonymous variant, so the missense-specific in silico rules (PP3 missense, BP4 missense) are not applicable.

ClinVar classifies this variant as Likely Benign (VariationID 184944, reviewed by the ClinGen HBOP Expert Panel). The variant has been reported as Likely Benign by two clinical laboratories and Benign by one clinical laboratory.

No functional studies, case-control data, segregation data, or co-occurrence observations involving this specific variant were identified in the literature. Publications reviewed (PMID 34242744, 15604628, 17508274, 18163131, 20301317) did not contain variant-specific evidence for NM_000051.3:c.5544T>C.

Evidence summary: PM2_Supporting (1 pathogenic supporting) versus BP4_Supporting and BP7_Supporting (2 benign supporting). Under the CSPEC HBOP v1.5.0 combination rules, the presence of both pathogenic and benign supporting criteria triggers Rule 31, yielding a classification of Uncertain Significance — Conflicting Evidence.