chr17-61801348-C-G

Variant names:

• chr17-61801348-C-G
• rs149364097
• NM_032043.3:c.1045G>C

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PP3_Moderate PP5_Very_Strong

The NM_032043.3(BRIP1):​c.1045G>C​(p.Ala349Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,613,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000186543: Functional studies revealed that this alteration has significantly impaired helicase activity leading to decreased cell survival upon exposure to DNA damaging agents (Wu Y et al. Blood. 2010" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A349S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: BRIP1 NM_032043.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15 O:1
• Conservation: PhyloP100: 2.77
• Publications: 44 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: Illumina, Orphanet
• Fanconi anemia complementation group J

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

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

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000186543: Functional studies revealed that this alteration has significantly impaired helicase activity leading to decreased cell survival upon exposure to DNA damaging agents (Wu Y et al. Blood. 2010; 116(19):3780-91); Sommers JA et al. J. Biol. Chem. 2014 Jul; 289(29):19928-41).; SCV001357009: Functional studies have reported this variant as a dominant negative mutation, with the mutant protein exhibiting defective helicase activity and impaired response to DNA damaging agent (PMID: 16973432, 20639400, 20980836, 23935105, 24895130, 27107905, 31822495).; SCV000547344: Experimental studies have shown that this missense change affects BRIP1 function (PMID: 16973432, 20639400, 27107905, 33619228).; SCV001426801: Multiple functional studies report the A349P variant affects protein function based on abolished helicase activity, DNA binding activity, translocase activity and effects of MMC on chromosome fragmentation, cell viability, and cell cycle, but has normal protein stability (Rudolf_2006, Wu_2009, Guo_2016, Sommers_2014, Moyer_2019, Odermatt_2020).; SCV004044084: Functional studies indicate this variant impacts protein function [PMID: 20639400].; SCV000807119: Experimental studies indicate that this variant impacts protein function (Rudolf et al. 2006. PubMed ID: 16973432; Wu et al. 2009. PubMed ID: 19519404; Guo et al. 2016. PubMed ID: 27107905; Sommers et al. 2014. PubMed ID: 24895130; Moyer et al. 2019. PubMed ID: 31822495).
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.878
• PP5: Variant 17-61801348-C-G is Pathogenic according to our data. Variant chr17-61801348-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 30535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRIP1	NM_032043.3	MANE Select	c.1045G>C	p.Ala349Pro	missense	Exon 8 of 20	NP_114432.2	Q9BX63-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRIP1	ENST00000259008.7	TSL:1 MANE Select	c.1045G>C	p.Ala349Pro	missense	Exon 8 of 20	ENSP00000259008.2	Q9BX63-1
	BRIP1	ENST00000682453.1		c.1045G>C	p.Ala349Pro	missense	Exon 9 of 21	ENSP00000506943.1	Q9BX63-1
	BRIP1	ENST00000683039.1		c.1045G>C	p.Ala349Pro	missense	Exon 9 of 21	ENSP00000508303.1	Q9BX63-1

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152040 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251328 AF XY: 0.00

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000335 AC: 49 AN: 1461772 Hom.: 0 Cov.: 32 AF XY: 0.0000261 AC XY: 19 AN XY: 727188

African (AFR) AF: 0.0000598 AC: 2 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000396 AC: 44 AN: 1111928

Other (OTH) AF: 0.0000331 AC: 2 AN: 60392

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 152040 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74248

African (AFR) AF: 0.0000966 AC: 4 AN: 41404

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000565 Hom.: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Hereditary cancer-predisposing syndrome (4)
3	-	-	Fanconi anemia complementation group J (3)
2	-	-	Familial cancer of breast (2)
1	-	-	BRIP1-related disorder (1)
1	-	-	Diffuse intrinsic pontine glioma (1)
1	-	-	Familial cancer of breast;C1836860:Fanconi anemia complementation group J (1)
1	-	-	Familial ovarian cancer (1)
1	-	-	Hereditary breast ovarian cancer syndrome (1)
1	-	-	not provided (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	-0.084	T
MutationAssessor	Benign	1.9	L
PhyloP100		2.8
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.64
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.041	D
Polyphen		1.0	D
Vest4		0.78
MVP		0.85
MPC		0.66
ClinPred		0.89	D
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.76
gMVP		0.76
Mutation Taster		=24/76	disease causing (ClinVar)

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: rs149364097; hg19: chr17-59878709;