chr17-61686113-ACT-GCC

Variant names:

• chr17-61686113-ACT-GCC
• NM_032043.3:c.2626_2628delAGTinsGGC
• BRIP1 p.Ser876Gly

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_032043.3(BRIP1):c.2626_2628delAGTinsGGC (p.Ser876Gly) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.S876G: Uncertain_significance (ClinVar VariationId 530349, 2 stars); p.S876N: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 483140); p.S876R: Uncertain_significance (ClinVar VariationId 421096, 2 stars); p.S876R: Uncertain_significance (ClinVar VariationId 2952700, 1 star); p.S876= (synonymous): Benign/Likely_benign (ClinVar VariationId 1332631, 2 stars)

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRIP1 NM_032043.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.42
• Publications: 0 publications found

Genes affected

BRIP1 (HGNC:20473): (BRCA1 interacting DNA helicase 1) The protein encoded by this gene is a member of the RecQ DEAH helicase family and interacts with the BRCT repeats of breast cancer, type 1 (BRCA1). The bound complex is important in the normal double-strand break repair function of breast cancer, type 1 (BRCA1). This gene may be a target of germline cancer-inducing mutations. [provided by RefSeq, Jul 2008]

BRIP1 Gene-Disease associations (from GenCC):

• familial ovarian cancer

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Fanconi anemia

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina
• Fanconi anemia complementation group J

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen
• hereditary breast carcinoma

  Inheritance: AD Classification: STRONG, LIMITED, NO_KNOWN Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• colorectal adenoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (base 0.0001, raised to 0.000287 by highest known P/LP ClinVar AF 0.000287) — PM2 moderate.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_032043.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	BRIP1 NM_032043.3	MANE Select	c.2626_2628delAGTinsGGC p.Ser876Gly	missense	N/A	Prot: NP_114432.2 UniProt:

BRIP1 NM_032043.3

MANE Select

HGVSc / HGVSpc.2626_2628delAGTinsGGCp.Ser876Gly

Exon rankN/A

missense

Prot: NP_114432.2UniProt: Q9BX63-1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	BRIP1 ENST00000259008.7	TSL:1MANE Select	c.2626_2628delAGTinsGGC p.Ser876Gly	missense	N/A	Prot: ENSP00000259008.2 UniProt:
	BRIP1 ENST00000682453.1		c.2626_2628delAGTinsGGC p.Ser876Gly	missense	N/A	Prot: ENSP00000506943.1 UniProt:
	BRIP1 ENST00000683039.1		c.2626_2628delAGTinsGGC p.Ser876Gly	missense	N/A	Prot: ENSP00000508303.1 UniProt:

BRIP1 ENST00000259008.7

TSL:1MANE Select

HGVSc / HGVSpc.2626_2628delAGTinsGGCp.Ser876Gly

Exon rankN/A

missense

Prot: ENSP00000259008.2UniProt: Q9BX63-1

BRIP1 ENST00000682453.1

HGVSc / HGVSpc.2626_2628delAGTinsGGCp.Ser876Gly

Exon rankN/A

missense

Prot: ENSP00000506943.1UniProt: Q9BX63-1

BRIP1 ENST00000683039.1

HGVSc / HGVSpc.2626_2628delAGTinsGGCp.Ser876Gly

Exon rankN/A

missense

Prot: ENSP00000508303.1UniProt: Q9BX63-1

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Benign	3.4

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

hg19: chr17-59763474;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar