NM_032043.3:c.2085G>A is a synonymous variant in exon 14 of BRIP1 encoding p.Leu695=, predicting no amino acid change. SpliceAI predicts no impact on splicing (max delta score 0.00), supporting a benign interpretation (BP4_Supporting, BP7_Supporting).1 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, though absence from population databases does not independently support either benign or pathogenic interpretation for a synonymous variant.2 ClinVar classifies this variant as Likely benign (VariationID 530367) based on submissions from three clinical diagnostic laboratories (BP6_Supporting).3 No variant-specific functional data, segregation data, case-control studies, or de novo observations were identified in the literature. No paper reviewed directly mentions NM_032043.3:c.2085G>A. Applying generic ACMG/AMP 2015 classification rules: BP6_Supporting + BP7_Supporting result in Likely Benign (at least two supporting benign criteria).4
BRIP1
Final classification
Likely Benign
BRIP1 c.2085G>A · p.Leu695=
BRIP1
NM_032043.3:c.2085G>A is a synonymous variant in exon 14 of BRIP1 encoding p.Leu695=, predicting no amino acid change.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BP4 supporting, BP6 supporting, BP7 supporting; combination = 3 supporting benign, which maps to Likely Benign.
Classification rationale
BP4BP6BP7
Likely Benign
BRIP1 c.2085G>A
BP4 + BP6 + BP7
→
Likely Benign
Gene diagram
· NM_032043.3 · variants mapped to exon structure
BRIP1
NM_032043.3
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 17 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
BP4
supporting
Benign
SpliceAI predicts no splicing impact for this synonymous variant (max delta score 0.00 across all acceptor and donor positions). REVEL and BayesDel do not provide scores for synonymous variants. The available computational evidence, while limited to splicing prediction, supports a benign interpretation.
SpliceAI max delta score = 0.00no predicted disruption of splicing.
✓
BP6
supporting
Benign
ClinVar reports NM_032043.3:c.2085G>A as Likely benign (VariationID 530367), based on submissions from three clinical diagnostic laboratories (Color Health, Invitae/Labcorp, Ambry Genetics). Multiple reputable clinical laboratories have independently classified this variant as likely benign, meeting BP6 criteria for a reputable source reporting the variant as benign.
ClinVar Likely benign classification (3 clinical laboratories): Color Health (SCV001347440)Labcorp/Invitae (SCV000757640)Ambry Genetics (SCV006208078).
✓
BP7
supporting
Benign
NM_032043.3:c.2085G>A is a synonymous variant at codon 695 (p.Leu695=) in exon 14 of BRIP1. SpliceAI predicts no impact on splicing (all delta scores = 0.00; donor/acceptor gain/loss scores all at zero). The variant is not located in a highly conserved splice region. BP7 is met for a synonymous variant with no predicted effect on splicing.
Synonymous variant (p.Leu695=) at exon 14 positionSpliceAI max delta score = 0.00no predicted alteration of native splice sites.
Assessed · not applied
Pathogenic
PS2
No de novo data are available for this variant.
PS3
No well-established functional studies demonstrating a deleterious effect have been identified for this variant.
PS4
No case-control or case-series prevalence data are available for this variant.
PM1
This synonymous variant is not located in a statistically significant mutational hotspot or a well-established functional domain without benign variation.
PM2
While this variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, PM2 is not applied to synonymous variants with no predicted splice impact because the variant class (synonymous, predicted neutral by SpliceAI) explains its rarity and does not support a pathogenic interpretation.
PM6
No assumed de novo data are available for this variant.
PP1
No co-segregation data are available for this variant.
PP3
In silico tools do not predict a deleterious effect.
PP4
No patient phenotype or family history data specific to this variant are available.
PP5
PP5 requires a reputable source to report the variant as pathogenic.
Benign
BA1
This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS1
This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS2
No data are available regarding observation of this variant in healthy adult individuals for a fully penetrant disorder.
BS3
No well-established functional studies demonstrating no damaging effect have been identified for this variant.
BS4
No segregation data are available for this variant.
BP2
No data are available regarding observation of this variant in trans with a pathogenic variant for a fully penetrant dominant disorder.
BP5
No data are available regarding an alternate molecular basis for disease in individuals carrying this variant.
N/A · 5
PVS1 · PS1 · PM5 · PP2 · BP1
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Likely benign (3 clinical laboratories). (ClinVarID = 530367)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
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
Triaged references · 7 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
31429903 ↗
Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer: US Preventive Services Task Force Recommendation Statement.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR