NM_032043.3:c.2085G>A

BRIP1 · NP_114432.2:p.(Leu695=) · NM_032043.3

GRCh37: chr17:59853774 C>T · GRCh38: chr17:61776413 C>T

Gene: BRIP1 Transcript: NM_032043.3

Final call

Likely Benign

BP4 supporting BP6 supporting BP7 supporting

Variant details

Gene

BRIP1

Transcript

NM_032043.3

Protein

NP_114432.2:p.(Leu695=)

gnomAD AF

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

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.

ClinVar classifies this variant as Likely benign (VariationID 530367) based on submissions from three clinical diagnostic laboratories (BP6_Supporting).

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).

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting 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	NM_032043.3:c.2085G>A is a synonymous variant (p.Leu695=), not a null variant (nonsense, frameshift, or canonical splice site). PVS1 is reserved for variants predicted to cause loss of function via transcript nonsense-mediated decay or truncation.	pvs1_variant_assessment
PS1	N/A	This is a synonymous variant producing no amino acid change. PS1 requires the same amino acid change as a previously established pathogenic variant, which is not applicable to synonymous variants.
PS2	Not assessed	No de novo data are available for this variant. PS2 requires confirmation of both maternity and paternity in a patient with disease and no family history.
PS3	Not met	No well-established functional studies demonstrating a deleterious effect have been identified for this variant. The literature reviewed (PMID:25741868, PMID:31429903) contains no variant-specific functional data.
PS4	Not assessed	No case-control or case-series prevalence data are available for this variant. PS4 requires a statistically significant enrichment in affected individuals compared to controls.
PS5	Not met	PS5 is not a standard ACMG/AMP 2015 criterion. To the extent it is interpreted as a reputable source reporting the variant as pathogenic, no such evidence exists; ClinVar reports Likely benign, and no source has classified this variant as pathogenic.	clinvar
PM1	Not met	This synonymous variant is not located in a statistically significant mutational hotspot or a well-established functional domain without benign variation. Hotspot analysis returned negative.
PM2	Not met	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. The absence from population databases is expected for rare neutral variants.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	This is a synonymous variant (p.Leu695=), not a missense change. PM5 requires a novel missense variant at the same amino acid residue as a known pathogenic missense variant. pm5_candidates.json confirms no eligible comparator candidates.	pm5_candidates
PM6	Not assessed	No assumed de novo data are available for this variant. PM6 requires a de novo observation without confirmation of paternity and maternity.
PP1	Not assessed	No co-segregation data are available for this variant. PP1 requires co-segregation with disease in multiple affected family members.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation and where missense is a common disease mechanism. This variant is synonymous (p.Leu695=), not missense.
PP3	Not met	In silico tools do not predict a deleterious effect. REVEL and BayesDel scores are not available for this synonymous variant. SpliceAI predicts no splicing impact (max delta score 0.00). Multiple lines of computational evidence do not support pathogenicity.	spliceai
PP4	Not assessed	No patient phenotype or family history data specific to this variant are available. PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology.
PP5	Not met	PP5 requires a reputable source to report the variant as pathogenic. ClinVar classifies NM_032043.3:c.2085G>A as Likely benign (VariationID 530367) based on three clinical laboratory submissions. No source classifies this variant as pathogenic.	clinvar
BA1	Not met	This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. BA1 requires an allele frequency >1% in population databases (non-VCEP threshold). The variant does not meet this threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. BS1 requires an allele frequency >0.3% in population databases (non-VCEP threshold). The variant does not meet this threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	No data are available regarding observation of this variant in healthy adult individuals for a fully penetrant disorder. BS2 requires observation in a healthy adult homozygous or hemizygous individual for a fully penetrant early-onset disorder.
BS3	Not assessed	No well-established functional studies demonstrating no damaging effect have been identified for this variant. The literature reviewed contains no variant-specific functional data.
BS4	Not assessed	No segregation data are available for this variant. BS4 requires lack of segregation with disease in affected family members.
BP1	N/A	BP1 applies to missense variants in genes where only truncating variants cause disease. This variant is synonymous (p.Leu695=), not missense.
BP2	Not assessed	No data are available regarding observation of this variant in trans with a pathogenic variant for a fully penetrant dominant disorder.
BP4	Met	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
BP5	Not assessed	No data are available regarding an alternate molecular basis for disease in individuals carrying this variant.
BP6	Met	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
BP7	Met	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.	spliceai

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