NM_032043.3:c.3069C>T

BRIP1 · NP_114432.2:p.(Leu1023=) · NM_032043.3

GRCh37: chr17:59761338 G>A · GRCh38: chr17:61683977 G>A

Gene: BRIP1 Transcript: NM_032043.3

Final call

VUS

PM2 moderate BP7 supporting benign

Variant details

Gene

BRIP1

Transcript

NM_032043.3

Protein

NP_114432.2:p.(Leu1023=)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The BRIP1 c.3069C>T (p.Leu1023=, p.L1023=) variant has been reported in ClinVar predominantly as likely benign or benign.

This variant is present at low frequency in gnomAD, with overall allele frequencies of 0.01061% in v2.1 and 0.00836% in v4.1, and highest observed South Asian frequencies of 0.06533% and 0.04721%, respectively; these values are below the default 0.1% PM2 threshold and below the 0.3% BS1 and 1% BA1 benign thresholds.

This synonymous variant is predicted to have no significant splice effect, with a SpliceAI maximum delta score of 0.01, which supports BP7 and argues against PP3.

Final determination: Generic ACMG/AMP 2015 fallback rules identified both pathogenic and benign evidence, so the overall classification remains Variant of Uncertain Significance because the evidence is conflicting.

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	BRIP1 loss of function is an established germline disease mechanism, but c.3069C>T is a synonymous variant and does not fall into the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1,2 splice variants; therefore PVS1 is not applicable.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	No evidence was identified showing that a different nucleotide change producing the same amino acid alteration has been established as pathogenic, so PS1 was not assessed.
PS2	Not assessed	No confirmed de novo occurrence with verified parentage was identified, so PS2 was not assessed.
PS3	Not assessed	No well-established functional studies demonstrating a damaging effect of this specific variant were identified, so PS3 was not assessed.
PS4	Not assessed	No case-control or enrichment data were identified showing this variant is significantly more common in affected individuals than in controls, so PS4 was not assessed.	clinvar
PM1	Not met	Available evidence does not support location in a well-established mutational hotspot or critical functional domain without benign variation. Cancer Hotspots did not identify a significant hotspot at residue L1023, and OncoKB did not show variant-specific oncogenic curation.	hotspots oncokb
PM2	Met	This variant is present at low frequency in population databases. The highest observed population frequency is 0.06533% in gnomAD v2.1 South Asian samples and 0.04721% in gnomAD v4.1 South Asian samples, both below the default 0.1% PM2 threshold, which supports PM2 under the generic fallback framework.	gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified showing this variant in trans with a pathogenic variant for a recessive disorder, so PM3 was not assessed.
PM4	N/A	This is a synonymous variant and does not change protein length, so PM4 is not applicable.
PM5	N/A	PM5 applies to novel missense changes at an amino acid residue where a different pathogenic missense change is known. This variant is synonymous, so PM5 is not applicable.
PM6	Not assessed	No assumed de novo occurrence was identified, so PM6 was not assessed.
PP1	Not assessed	No segregation data were identified for this variant, so PP1 was not assessed.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation and where missense variants are a common disease mechanism. This variant is synonymous, so PP2 is not applicable.
PP3	Not met	Available computational evidence does not support a deleterious effect on splicing. SpliceAI shows a maximum delta score of 0.01, which is consistent with no significant splice impact, so PP3 is not met.	spliceai
PP4	Not assessed	No phenotype or family history data sufficiently specific for a single genetic cause were identified for this variant, so PP4 was not assessed.
PP5	Not met	No reputable source classification supporting pathogenicity was identified. ClinVar submissions for this variant are benign or likely benign, so PP5 is not met.	clinvar
BA1	Not met	Population frequency does not reach the standalone benign threshold. The highest observed population frequency is 0.06533% in gnomAD v2.1 and 0.04721% in gnomAD v4.1, both below the 1% BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Population frequency does not exceed the strong benign threshold. The highest observed population frequency is 0.06533% in gnomAD v2.1 and 0.04721% in gnomAD v4.1, both below the default 0.3% BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in healthy adult individuals in a way that is sufficient to apply BS2, so BS2 was not assessed.
BS3	Not assessed	No well-established functional studies demonstrating no damaging effect of this specific variant were identified, so BS3 was not assessed.
BS4	Not assessed	No segregation studies showing lack of segregation with disease were identified, so BS4 was not assessed.
BP1	N/A	BP1 applies to missense variants in genes where truncating variants are the primary disease mechanism. This variant is synonymous, so BP1 is not applicable.
BP2	Not assessed	No phase data showing this variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant were identified, so BP2 was not assessed.
BP3	N/A	BP3 applies to in-frame indels in repetitive regions without known function. This variant is synonymous, so BP3 is not applicable.
BP4	N/A	BP4 is generally used for missense or other sequence changes with multiple computational predictors supporting no impact. For this synonymous variant, the splice prediction evidence is captured under BP7 instead.	spliceai
BP5	Not assessed	No evidence was identified for an alternate molecular basis explaining disease in carriers of this variant, so BP5 was not assessed.
BP6	Not met	Although ClinVar reports this variant as benign or likely benign, those submissions are listed with criteria provided rather than as unsupported assertions from a reputable source, so BP6 was not applied.	clinvar
BP7	Met	This is a synonymous BRIP1 variant, p.(Leu1023=), and available splicing prediction does not indicate a meaningful splice effect. SpliceAI shows a maximum delta score of 0.01, supporting no significant splice impact, which meets BP7.	spliceai

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