17-61685921-C-G

Variant names:

• chr17-61685921-C-G
• rs786201396
• NM_032043.3:c.2820G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032043.3(BRIP1):​c.2820G>C​(p.Lys940Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. K940K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BRIP1 NM_032043.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.656
• Publications: 0 publications found

Genes affected

BRIP1 (HGNC:20473): (BRCA1 interacting 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, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hereditary breast carcinoma

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

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13396013).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRIP1	NM_032043.3	c.2820G>C	p.Lys940Asn	missense_variant	Exon 19 of 20	ENST00000259008.7	NP_114432.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRIP1	ENST00000259008.7	c.2820G>C	p.Lys940Asn	missense_variant	Exon 19 of 20	1	NM_032043.3	ENSP00000259008.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

May 11, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting, BP4_Moderate c.2820G>C, located in exon 19 of the BRIP1 gene, is predicted to result in the substitution of Lysine by Asparagine at codon 940, p.(Lys940Asn). It is not present in the population database gnomAD v2.1.1, non cancer dataset (PM2_supporting). The SpliceAI algorithm predicts no significant impact on splicing. The REVEL meta-predictor score for this variant (0.066) suggests that it does not affect the protein function according Pejaver 2022 thresholds (PMID: 36413997) (BP4_moderate). To our knowledge, neither relevant clinical data nor well-stablished functional studies have been reported for this variant. This variant has only been reported once in ClinVar, as an uncertain significance variant. Based on the currently available information, c.2820G>C is classified as an uncertain significance variant according to ACMG guidelines.

May 17, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.K940N variant (also known as c.2820G>C), located in coding exon 18 of the BRIP1 gene, results from a G to C substitution at nucleotide position 2820. The lysine at codon 940 is replaced by asparagine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

Familial cancer of breast;C1836860:Fanconi anemia complementation group J Uncertain:1

Jan 15, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 940 of the BRIP1 protein (p.Lys940Asn). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.25	T;.
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.50	T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.9	L;L
PhyloP100		0.66
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.45	N;.
REVEL	Benign	0.066
Sift	Benign	0.077	T;.
Sift4G	Benign	0.28	T;T
Vest4		0.23
ClinPred		0.15	T
GERP RS		3.1
Varity_R		0.061
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs786201396; hg19: chr17-59763282;