rs397507722

Variant names:

• chr13-32326124-A-C
• rs397507722
• NM_000059.4:c.449A>C

Your query was ambiguous. Multiple possible variants found:

• chr13-32326124-A-C
• chr13-32326124-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000059.4(BRCA2):​c.449A>C​(p.His150Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,740 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H150R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.0640
• Publications: 8 publications found

Genes affected

BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]

BRCA2 Gene-Disease associations (from GenCC):

• BRCA2-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• breast-ovarian cancer, familial, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Fanconi anemia complementation group D1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• pancreatic cancer, susceptibility to, 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• medulloblastoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 39 uncertain in NM_000059.4
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000059.4. 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
	BRCA2	NM_000059.4	MANE Select	c.449A>C	p.His150Pro	missense	Exon 5 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.449A>C	p.His150Pro	missense	Exon 5 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.449A>C	p.His150Pro	missense	Exon 5 of 27	NP_001393649.1	A0A8V8TPZ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.449A>C	p.His150Pro	missense	Exon 5 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.449A>C	p.His150Pro	missense	Exon 5 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.80A>C	p.His27Pro	missense	Exon 5 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457740 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725320

African (AFR) AF: 0.00 AC: 0 AN: 33366

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39556

South Asian (SAS) AF: 0.00 AC: 0 AN: 86042

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.000218 AC: 1 AN: 4578

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109806

Other (OTH) AF: 0.00 AC: 0 AN: 60168

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary breast ovarian cancer syndrome (1)
-	1	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	6.8
DANN	Benign	0.26
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.049	N
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.86	T
PhyloP100		0.064
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.16
Sift	Benign	0.097	T
Sift4G	Benign	0.19	T
Vest4		0.52
MutPred		0.38		Loss of catalytic residue at H150 (P = 0.0142)
MVP		0.85
MPC		0.12
ClinPred		0.14	T
GERP RS		2.2
gMVP		0.41
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397507722; hg19: chr13-32900261;