chr17-61686115-T-A

Variant names:

• chr17-61686115-T-A
• rs1555573469
• NM_032043.3:c.2626A>T
• BRIP1 p.Ser876Cys

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.2626A>T (p.Ser876Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. 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: 2.60
• Publications: 1 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.2626A>T p.Ser876Cys	missense	Exon 19 of 20	Prot: NP_114432.2 UniProt:

BRIP1 NM_032043.3

MANE Select

HGVSc / HGVSpc.2626A>Tp.Ser876Cys

Exon rankExon 19 of 20

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.2626A>T p.Ser876Cys	missense	Exon 19 of 20	Prot: ENSP00000259008.2 UniProt:
	BRIP1 ENST00000682453.1		c.2626A>T p.Ser876Cys	missense	Exon 20 of 21	Prot: ENSP00000506943.1 UniProt:
	BRIP1 ENST00000683039.1		c.2626A>T p.Ser876Cys	missense	Exon 20 of 21	Prot: ENSP00000508303.1 UniProt:

BRIP1 ENST00000259008.7

TSL:1MANE Select

HGVSc / HGVSpc.2626A>Tp.Ser876Cys

Exon rankExon 19 of 20

missense

Prot: ENSP00000259008.2UniProt: Q9BX63-1

BRIP1 ENST00000682453.1

HGVSc / HGVSpc.2626A>Tp.Ser876Cys

Exon rankExon 20 of 21

missense

Prot: ENSP00000506943.1UniProt: Q9BX63-1

BRIP1 ENST00000683039.1

HGVSc / HGVSpc.2626A>Tp.Ser876Cys

Exon rankExon 20 of 21

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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:34
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	19
AlphaMissense	Benign	0.085
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.88	D
FuncVEP CTI	Benign	0.20
GPN-Star LLR	N/A	-6.0
GPN-Star score	N/A	6.0
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	-0.016	T
MutationAssessor	Uncertain	2.1	M
PhyloP100	Benign	2.6
popEVE	Benign	-3.7
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.37
Sift	Benign	0.032	D
Sift4G	Uncertain	0.052	T
Varity_R	N/A	0.26
VESM-3B	Benign	-6.7

Showing 27 of 27 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

dbSNP: rs1555573469;

hg19: chr17-59763476;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar